Diketo-Piperazine and Piperidine derivatives as antiviral agents

ABSTRACT

This disclosure provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the disclosure is concerned with diketo piperazine and piperadine derivatives that possess unique antiviral activity. More particularly, the present disclosure relates to compounds useful for the treatment of HIV and AIDS.

RELATED APPLICATIONS

This application is a continuation-in-part of pending U.S. patentapplication Ser. No. 11/733,283 filed Apr. 10, 2007 which claimspriority to U.S. provisional application Ser. No. 60/794,700 filed onApr. 25, 2006 and to U.S. provisional application Ser. No. 60/794,703filed on Apr. 25, 2006.

FIELD OF THE DISCLOSURE

This disclosure provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and method of use.

In particular, the disclosure is concerned with diketo piperazine andpiperidine derivatives that possess unique antiviral activity. Moreparticularly, the present disclosure relates to compounds useful for thetreatment of HIV and AIDS.

BACKGROUND ART

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 40 million people infected worldwide at theend of 2005. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0million new infections were reported, and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV includenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations: zidovudine (or AZT or Retrovir®), didanosine (or Videx®),stavudine (or Zerit®), lamivudine (or 3TC or Epivir®), zalcitabine (orDDC or Hivid®), abacavir succinate (or Ziagen®), Tenofovir disoproxilfumarate salt (or Viread®), emtricitabine (or FTC), Combivir® (contains−3TC plus AZT), Trizivir® (contains abacavir, lamivudine, andzidovudine), Epzicom® (contains abacavir and lamivudine), Truvada®(contains Viread® and emtricitabine); non-nucleoside reversetranscriptase inhibitors: nevirapine (or Viramune®), delavirdine (orRescriptor®) and efavirenz (or Sustiva®), and peptidomimetic proteaseinhibitors or approved formulations: saquinavir, indinavir, ritonavir,nelfinavir, amprenavir, lopinavir, and Kaletra® (lopinavir andRitonavir). Each of these drugs can only transiently restrain viralreplication if used alone. However, when used in combination, thesedrugs have a profound effect on viremia and disease progression. Infact, significant reductions in death rates among AIDS patients havebeen recently documented as a consequence of the widespread applicationof combination therapy. However, despite these impressive results, 30 to50% of patients ultimately fail combination drug therapies. Insufficientdrug potency, non-compliance, restricted tissue penetration anddrug-specific limitations within certain cell types (e.g. mostnucleoside analogs cannot be phosphorylated in resting cells) mayaccount for the incomplete suppression of sensitive viruses.Furthermore, the high replication rate and rapid turnover of HIV-1combined with the frequent incorporation of mutations, leads to theappearance of drug-resistant variants and treatment failures whensub-optimal drug concentrations are present. Therefore, novel anti-HIVagents exhibiting distinct resistance patterns, and favorablepharmacokinetic as well as safety profiles are needed to provide moretreatment options. Improved HIV fusion inhibitors and HIV entrycoreceptor antagonists are two examples of new classes of anti-HIVagents currently being studied by a number of investigators.

The properties of a class of HIV entry inhibitors called HIV attachmentinhibitors has been improved in an effort to obtain compounds withmaximized utility and efficacy as antiviral agents. A disclosuredescribing indoles of which the structure shown below for BMS-705 isrepresentative has been disclosed [Antiviral Indoleoxoacetyl PiperazineDerivatives].

Two other compounds, referred to in the literature as BMS-806 andBMS-043 have been described in both the academic and patent art:

Some description of their properties in human clinical trials have beendisclosed in literature.

It should be noted that in all three of these structures, a piperazineamide (In these three structures a piperazine phenyl amide) is presentand this group is directly attached to an oxoacetyl moiety. Theoxoacetyl group is attached at the 3-position of 4-Fluoro indole inBMS-705 and to the 3 position of substituted azaindoles in BMS-806 andBMS-043.

In an effort to obtain improved anti-HIV compounds, later publicationsdescribed in part, modified substitution patterns on the indoles andazaindoles. Examples of such effort include: (1) novel substitutedindoleoxoacetic piperazine derivatives, (2) substitutedpiperazinyloxoacetylindole derivatives, and (3) substitutedazaindoleoxoacetic piperazine derivatives.

Replacement of these groups with other heteroaromatics or substitutedheteroaromatics or bicyclic hydrocarbons was also shown to be feasible.Examples include: (1) indole, azaindole and related heterocyclicamidopiperazine derivatives; (2) bicyclo 4.4.0 antiviral derivatives;and (3) diazaindole derivatives.

A select few replacements for the piperazine amide portion of themolecules have also been described in the art and among these examplesare (1) some piperidine alkenes; (2) some pyrrolidine amides; (3) someN-aryl or heteroaryl piperazines; (4) some piperazinyl ureas; and (5)some carboline containing compounds.

Method(s) for preparing prodrugs for this class of compounds wasdisclosed in Prodrugs of piperazine and Substituted Piperidine AntiviralAgents (Ueda et al., U.S. non-provisional application Ser. No.11/066,745, filed Feb. 25, 2005 or US20050209246A1 or WO2005090367A1).

A published PCT patent application WO2003103607A1 (Jun. 11, 2003)disclosures an assay useful for assaying some HIV inhibitors.

Several published patent applications describe combination studies withpiperazine benzamide inhibitors, for example, US20050215543(WO2005102328A1), US20050215544 (WO2005102391A1), and US20050215545(WO2005102392A2).

A publication on new compounds in this class of attachment inhibitors(Jinsong Wang et. al. Org. Biol. Chem. 2005, 3, 1781-1786.) and a patentapplication on some more remotely related compounds have appearedWO2005/016344 published on Feb. 24, 2005.

Published patent applications WO2005/016344 and WO2005/121094 alsodescribe piperazine derivatives which are HIV inhibitors. The compoundsdescribed in these applications are structurally distinct from thecompounds of the present disclosure.

Nothing in these references can be construed to disclose or suggest thenovel compounds of this disclosure and their use to inhibit HIVinfection.

SUMMARY OF THE DISCLOSURE

The present disclosure relates to compounds of Formula I, thepharmaceutically acceptable salts and/or solvates (e.g., hydrates)thereof, their pharmaceutical formulations, and their use in patientssuffering from or susceptible to a virus such as HIV. The compounds ofFormula I, their pharmaceutically acceptable salts and/or solvate areeffective antiviral agents, particularly as inhibitors of HIV. They areuseful for the treatment of HIV and AIDS.

One embodiment of the present disclosure is directed to a compound ofFormula I, or pharmaceutically acceptable salts thereof,

wherein:A is selected from the group consisting of:

wherein- - represents a carbon-carbon bond or does not exist;R¹ is hydrogen, C₁-C₄ alkyl, or C₁-C₄ fluoroalkyl;R² is hydrogen;R⁴, R⁵, R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, hydroxy, halogen, cyano, nitro, C₁-C₄ alkyl,C₁-C₄ fluoroalkyl, OR_(a), NR_(a)R_(b), COOR_(a), and Group B;R_(a) and R_(b) are each independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and Group B;R^(4N) is O or does not exist;Y is selected from the group consisting of phenyl, C₅-C₇ monocyclicheteroaryl, C₉-C₁₀ bicyclic aryl, C₉-C₁₀ bicyclic heteroaryl, C₄-C₇heteroalicyclic, and C₅-C₇ cycloalkyl wherein said heteroaryl orheteroalicyclic contains from 1 to 4 heteroatoms selected from O, N, andS and with the proviso when Y is a bicyclic heteroaryl both X and Y areattached to a common ring wherein said aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from oxo, hydroxyl, C₁-C₆ alkyl, —NR⁵⁵R⁵⁶, —OC₁-C₃ alkyl,—S—R₁, —S(O)₂R₁, CF₃, CN, wherein said C₁-C₆ alkyl can be optionallysubstituted with Group B;Z is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl, —COOR₃, 4, 5, or 6 membered ring cyclic N-lactam,—C(O)NR⁴²R⁴³, —C(O)R⁵⁷ wherein R⁵⁷ is optionally substituted with CN orGroup B; —NR⁵⁵R⁵⁶, aryl and heteroaryl; in which said aryl is phenyl;said heteroaryl is selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, imidazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and C₉-C₁₀ bicyclicheteroaryl with 1-4 heteroatom(s); said aryl or heteroaryl is optionallysubstituted with one or two of the same or different members selectedfrom the group consisting of amino, nitro, cyano, hydroxy, C₁₋₆ alkoxy,—C(O)NH₂, C₁₋₆ alkyl, —NHC(O)CH₃, halogen, trifluoromethyl and Group B;Group B is selected from the group consisting of —C(O)NR⁴⁰R⁴¹, aryl,heteroaryl, heteroalicyclic, C(O)R³, C(═N—O—R¹)R³, acetal, UR^(8a),(C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from the group F; wherein aryl is napthyl or substitutedphenyl; wherein heteroaryl is a mono or bicyclic system which containsfrom 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in afused bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is a 3 to 7 membered mono cyclic ring which may bepartially unsaturated and may be substituted by 1 or two oxo groups andmay contain from 1 to 2 heteroatoms in the ring skeleton and which maybe fused to a benzene or pyridine ring;or Group B is (C₁₋₆)alkyl and (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyland (C₂₋₆)alkenyl are independently optionally substituted with a memberselected from the group consisting of phenyl, heteroaryl or—C(O)NR⁵⁵R⁵⁶; or with from one to three same or different halogens;wherein heteroaryl is a monocyclic system which contains from 3 to 7ring atoms, including from 1 to 4 heteroatoms;Group F is selected from the group consisting of oxo, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)₂-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)₂-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)₂ NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the Group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;Group G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,non-aromatic heterocyclic with 1-2 hetero atoms, —NR⁴⁸C(O)—(C₁₋₆)alkyl,—NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl, —NR⁴⁸C(O)-heteroaryl,—NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N-lactam,—NR⁴⁸S(O)₂—(C₁₋₆)alkyl, —NR⁴⁸S(O)₂, —(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)₂-aryl,—NR⁴³S(O)₂-heteroaryl, —NR⁴⁸S(O)₂-heteroalicyclic, sulfinyl, sulfonyl,sulfonamide, NR⁴⁸R⁴⁹, (C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹,NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹, NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴,and (C₁₋₆)alkylCOOR⁵⁴; wherein aryl is phenyl; heteroaryl is amonocyclic system which contains from 3 to 7 ring atoms, including from1 to 4 heteroatoms; heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R³ is selected from the group consisting of C₁-C₄ alkyl, aryl,heteroaryl, and heteroalicyclic; wherein said C₁-C₄ alkyl, aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or with from one to three same ordifferent substituents selected from the group F;wherein for R³, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, are each independently selectedfrom the group consisting of hydrogen and (C₁₋₆)alkyl; wherein said(C₁₋₆)alkyl is optionally substituted with one to three same ordifferent halogens or one hydroxy or one O (C₁₋₆)alkyl or one NR⁵⁵R⁵⁶;or one of R⁹, R¹⁰ or one of R¹¹, R¹² may form respectively with one ofR¹⁵, R¹⁶ or one of R¹³, R¹⁴ a one, two or three atom bridged comprisedof alkyl or nitrogen atoms;X is N or CH, (when X is CH the configuration at the center X may beracemic or pure (R) or pure (S) configuration);U is selected from the group consisting of NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of (a)hydrogen; (b) (C₁₋₆)alkyl substituted with one to three same ordifferent halogens (c) (C₁₋₆)alkoxy, aryl, heteroaryl orheteroalicyclic; or R⁴⁰ and R⁴¹ taken together with the nitrogen towhich they are attached form a member selected from the group consistingof aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine,piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to two same ordifferent substituents selected from C₁-C₃alkyl, halogen, hydroxyl,—OR⁵⁵, —NR⁵⁵R⁵⁶; —C(O)NR⁵⁵R⁵⁶; wherein for R⁴⁰ and R⁴¹ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine(optionally substituted with Group B), 4-NMe piperazine, piperidine,azepine, and morpholine; and wherein said (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the Group G; whereinfor R⁴² and R⁴³ aryl is phenyl; heteroaryl is a monocyclic system whichcontains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is a member selected from the group consisting ofaziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁴⁶ is selected from the group consisting of H, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, halogen, phenyl,and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl and phenyl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different halogen, amino, OH, CN or NO₂;R⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl andphenyl; andwith the proviso that the compound of Formula (I) is not

In a preferred embodiment, R¹ is H.

In a preferred embodiment, R⁵ is H.

In a preferred embodiment, R^(4N) does not exist.

In a preferred embodiment, R⁴ is halogen or OR^(a).

In a preferred embodiment, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ areeach independently selected from the group consisting of hydrogen, C₁-C₄alkyl and C₁-C₄ fluoroalkyl.

In a preferred embodiment, A is

In a preferred embodiment, Y is phenyl.

In a preferred embodiment, Y is C₅-C₇ monocyclic heteroaryl.

In a preferred embodiment, Y is C₉-C₁₀ bicyclic aryl.

In a preferred embodiment, Y is C₉-C₁₀ bicyclic heteroaryl.

In a preferred embodiment, Y is C₄-C₇ heteroalicyclic.

In a preferred embodiment, Y is C₅-C₇ cycloalkyl.

In a preferred embodiment, Y is tetrazole, triazole, pyrazole,imidazole, pyridine, pyrazine, pyrimidine, or pyridazine.

Another embodiment of the present disclosure is a method for treatingmammals infected with a virus, especially wherein said virus is HIV,comprising administering to said mammal an antiviral effective amount ofa compound of Formula I, and one or more pharmaceutically acceptablecarriers, excipients or diluents. Optionally, the compound of Formula Ican be administered in combination with an antiviral effective amount ofan AIDS treatment agent selected from the group consisting of: (a) anAIDS antiviral agent; (b) an anti-infective agent; (c) animmunomodulator; and (d) HIV entry inhibitors.

Another embodiment of the present disclosure is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound ofFormula I and one or more pharmaceutically acceptable carriers,excipients, diluents and optionally in combination with an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) HIV entry inhibitors.

DETAILED DESCRIPTION OF THE DISCLOSURE

Since the compounds of the present disclosure, may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present disclosure includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof.

DEFINITIONS

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“C₁-C₄ fluoroalkyl” refers to F-substituted C₁-C₄ alkyl wherein at leastone H atom is substituted with F atom, and each H atom can beindependently substituted by F atom;

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,triazinyl, tetrazinyl, and tetrazolyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. Rings are selectedfrom those which provide stable arrangements of bonds and are notintended to encomplish systems which would not exist. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon triple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroaliacyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z as defined above and R^(x) being H or (C₁₋₆)alkyl.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ being(C₁₋₆)alkyl.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ being(C₁₋₆)alkyl.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), with R^(X) andR^(Y) independently being H or (C₁₋₆)alkyl.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group, with R_(x)being H or (C₁₋₆)alkyl.

A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) group, with R^(X)and R^(Y) independently being H or (C₁₋₆)alkyl.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ being (C₁₋₆)alkyl orphenyl.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) being(C₁₋₆)alkyl.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “4, 5, or 6 membered ring cyclic N-lactam” group refers to

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present disclosure are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Physiologically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this disclosure. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g. hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

In the method of the present disclosure, the term “antiviral effectiveamount” means the total amount of each active component of the methodthat is sufficient to show a meaningful patient benefit, i.e., healingof acute conditions characterized by inhibition of the HIV infection.When applied to an individual active ingredient, administered alone, theterm refers to that ingredient alone. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe therapeutic effect, whether administered in combination, serially orsimultaneously. The terms “treat, treating, treatment” as used hereinand in the claims means preventing or ameliorating diseases associatedwith HIV infection.

The present disclosure is also directed to combinations of the compoundswith one or more agents useful in the treatment of AIDS. For example,the compounds of this disclosure may be effectively administered,whether at periods of pre-exposure and/or post-exposure, in combinationwith effective amounts of the AIDS antivirals, immunomodulators,antiinfectives, or vaccines, such as those in the following table.

Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase (RT)inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC,in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIVin combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-MyersSquibb/ HIV infection, (CGP-73547) Novartis AIDS, ARC (proteaseinhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, (CGP-61755)Novartis AIDS, ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirusCurdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmuneCMV retinitis Immune globin Cytovene Syntex Sight threateningGanciclovir CMV peripheral CMV retinitis Delaviridine Pharmacia-UpjohnHIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem.AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddCHoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS,ARC (protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection,(DMP 266, Sustiva ®) AIDS, ARC (-)6-Chloro-4-(S)- (non-nucleoside RTcyclopropylethynyl- inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro-2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Famciclovir Smith Kline herpes zoster, herpes simplexFTC Emory University HIV infection, AIDS, ARC (reverse transcriptaseinhibitor) GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptaseinhibitor) HBY097 Hoechst Marion HIV infection, Roussel AIDS, ARC(non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm.HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS,Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC,asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer InstituteHIV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS,ARC (reverse transcriptase inhibitor); also with AZT LobucavirBristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine BoeheringerHIV infection, Ingleheim AIDS, ARC (RT inhibitor) Novapren NovaferonLabs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDSOctapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis,HIV Phosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (proteaseinhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection,AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection,LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-MyersSquibb HIV infection, AIDS, Didehydrodeoxy- ARC thymidine ValaciclovirGlaxo Wellcome Genital HSV & CMV infections Virazole Viratek/ICNasymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIVinfection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIVinfection, AIDS, ARC, Kaposi's sarcoma, in combination with othertherapies Tenofovir disoproxil, Gilead HIV infection, fumarate salt(Viread ®) AIDS, (reverse transcriptase inhibitor) Emtriva ®(Emtricitabine) Gilead HIV infection, AIDS, (reverse transcriptaseinhibitor) Combivir ® GSK HIV infection, AIDS, (reverse transcriptaseinhibitor) Abacavir succinate GSK HIV infection, (or Ziagen ®) AIDS,(reverse transcriptase inhibitor) Reyataz ® Bristol-Myers Squibb HIVinfection (or atazanavir) AIDs, protease inhibitor Fuzeon ®Roche/Trimeris HIV infection (or T-20) AIDs, viral Fusion inhibitorLexiva ® GSK/Vertex HIV infection (or Fosamprenavir calcium) AIDs, viralprotease inhibitor Maraviroc; (UK 427857) Pfizer HIV infection AIDs,(CCR5 antagonist, in development) Trizivir ® GSK HIV infection AIDs,(three drug combination) PA-457 Panacos HIV infection AIDs, (maturationInhibitor, in development) Sch-417690 (vicriviroc) Schering-Plough HIVinfection AIDs, (CCR5 antagonist, in development) TAK-652 Takeda HIVinfection AIDs, (CCR5 antagonist, in development) GSK 873140 GSK/ONO HIVinfection (ONO-4128) AIDs, (CCR5 antagonist, in development) BMS-707035Bristol-Myers Squibb HIV infection AIDs, (viral integrase Inhibitor)Integrase Inhibitor Merck HIV infection MK-0518 AIDs, viral integraseinhibitor in development Truvada ® Gilead Combination of Tenofovirdisoproxil fumarate salt (Viread ®) and Emtriva ® (Emtricitabine)Integrase Inhibitor Gilead/Japan Tobacco HIV Infection GS917/JTK-303AIDs, viral integrase inhibitor in development Triple drug combinationGilead/Bristol-Myers Squibb Combination of Tenofovir disoproxil fumaratesalt (Viread ®), Emtriva (Emtricitabine), and Sustiva ® (Efavirenz)IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia UpjohnAdvanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma FP-21399Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells Gamma InterferonGenentech ARC, in combination w/TNF (tumor necrosis factor) GranulocyteGenetics Institute AIDS Macrophage Colony Sandoz Stimulating FactorGranulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex StimulatingFactor Granulocyte Schering-Plough AIDS, Macrophage Colony combinationStimulating Factor w/AZT HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in Interleukin-2 CD4 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcomaMuramyl-Tripeptide Granulocyte Amgen AIDS, in combination ColonyStimulating w/AZT Factor Remune Immune Response Immunotherapeutic Corp.rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS,ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combinationw/AZT SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of Nystatin Pastille oral candidiasis Ornidyl MerrellDow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM& IV) (Rosemont, IL) Trimethoprim Antibacterial Trimethoprim/sulfaAntibacterial Piritrexim Burroughs Wellcome PCP treatment PentamidineFisons Corporation PCP prophylaxis Isethionate for Inhalation SpiramycinRhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm.Histoplasmosis; R51211 cryptococcal meningitis TrimetrexateWarner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcomaRecombinant Human Ortho Pharm. Corp. Severe anemia Erythropoietin assoc.with AZT therapy Recombinant Human Serono AIDS-related Growth Hormonewasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment ofanorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and NutritionPharmaceuticals malabsorption related to AIDS

Additionally, the compounds of the disclosure herein may be used incombination with another class of agents for treating AIDS which arecalled HIV entry inhibitors. Examples of such HIV entry inhibitors arediscussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol.9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5,May 2000, pp. 183-194 and Inhibitors of the entry of HIV into hostcells. Meanwell, Nicholas A.; Kadow, John F. Current Opinion in DrugDiscovery & Development (2003), 6(4), 451-461. Specifically thecompounds can be utilized in combination with other attachmentinhibitors, fusion inhibitors, and chemokine receptor antagonists aimedat either the CCR5 or CXCR4 coreceptor.

It will be understood that the scope of combinations of the compounds ofthis disclosure with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable but includes, in principle, any combination with anypharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with acompound of the present disclosure and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is Reyataz® (active ingredient Atazanavir).Typically a dose of 300 to 600 mg is administered once a day. This maybe co-administered with a low dose of Ritonavir (50 to 500 mgs). Anotherpreferred inhibitor of HIV protease is Kaletra®. Another usefulinhibitor of HIV protease is indinavir, which is the sulfate salt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include thosewith the following (1) indinavir with efavirenz, and, optionally, AZTand/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/orddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine.

In such combinations the compound of the present disclosure and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Preferred combinations are simultaneous or alternating treatments ofwith a compound of the present disclosure and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. Apreferred inhibitor of HIV protease is indinavir, which is the sulfatesalt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include thosewith the following (1) indinavir with efavirenz, and, optionally, AZTand/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/orddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine.

In such combinations the compound of the present disclosure and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

ABBREVIATIONS

The following abbreviations, most of which are conventionalabbreviations well known to those skilled in the art, are usedthroughout the description of the disclosure and the examples. Some ofthe abbreviations used are as follows:

-   -   h=hour(s)    -   rt=room temperature    -   mol=mole(s)    -   mmol=millimole(s)    -   g=gram(s)    -   mg=milligram(s)    -   mL=milliliter(s)    -   TFA=trifluoroacetic Acid    -   DCE=1,2-Dichloroethane    -   CH₂Cl₂=dichloromethane    -   TPAP=tetrapropylammonium perruthenate    -   THF=tetrahydrofuran    -   DEPBT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one    -   DMAP=4-dimethylaminopyridine    -   P-EDC=polymer supported        1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    -   EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    -   DMF=N,N-dimethylformamide    -   Hunig's Base=N,N-diisopropylethylamine    -   MCPBA=meta-chloroperbenzoic Acid    -   azaindole=1H-pyrrolo-pyridine    -   4-azaindole=1H-pyrrolo[3,2-b]pyridine    -   5-azaindole=1H-pyrrolo[3,2-c]pyridine    -   6-azaindole=1H-pyrrolo[2,3-c]pyridine    -   7-azaindole=1H-pyrrolo[2,3-b]pyridine    -   PMB=4-methoxybenzyl    -   DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone    -   OTf=trifluoromethanesulfonoxy    -   NMM=4-methylmorpholine    -   PIP-COPh=1-benzoylpiperazine    -   NaHMDS=sodium hexamethyldisilazide    -   EDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    -   TMS=trimethylsilyl    -   DCM=dichloromethane    -   DCE=dichloroethane    -   MeOH=methanol    -   THF=tetrahydrofuran    -   EtOAc=ethyl acetate    -   LDA=lithium diisopropylamide    -   TMP-Li=2,2,6,6-tetramethylpiperidinyl lithium    -   DME=dimethoxyethane    -   DIBALH=diisobutylaluminum hydride    -   HOBT=1-hydroxybenzotriazole    -   CBZ=benzyloxycarbonyl    -   PCC=pyridinium chlorochromate

The compounds of the present disclosure may be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand diluents.

Thus, in accordance with the present disclosure, there is furtherprovided a method of treating and a pharmaceutical composition fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition comprising a pharmaceutical carrier and atherapeutically effective amount of a compound of the presentdisclosure.

The pharmaceutical composition may be in the form of orallyadministrable suspensions or tablets; nasal sprays, sterile injectablepreparations, for example, as sterile injectable aqueous or oleagenoussuspensions or suppositories.

When administered orally as a suspension, these compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents, and lubricants known in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this disclosure can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weight individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

Chemistry

The present disclosure comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. General procedures toconstruct compounds of Formula I and intermediates useful for theirsynthesis are described in the following Schemes.

Chemistry Schemes:

Preparation of Compounds of Formula I

The preparation of template A-CO—CO—Cl and A-CO—CO—OH has been describedin detail in U.S. Pat. No. 6,469,006B1, U.S. Pat. No. 6,573,262B2, U.S.Pat. No. 6,900,323B2, US20050090522A1, U.S. Pat. No. 6,825,201,US20050261296A1, US20040186292A1, US20050267130A1, U.S. Pat. No.6,900,206B2, US20040063746, WO-00076521, WO-00162255, WO-00204440,WO-02062423, WO-02085301, WO-03068221 and US-2004/0063744.

A chemist skilled in the art is aware of many standard conditions forreacting an amine with an acyl halide 1 (Scheme 1) and carboxyl acid 4(Scheme 2) that could be used to convert the acid chloride or acid tothe desired amide products. Some general references of thesemethodologies and directions for use are contained in “ComprehensiveOrganic Transformation” by Richard C. Larock, Wiley-VCH, New York, 1989,972 (Carboxylic acids to amides), 979 (Acid halides to amides).

Scheme 1 depicts a general method for forming an amide from piperazineamidine 2 and acyl chloride 1. An appropriate base (from catalytic to anexcess amount) selected from sodium hydride, potassium carbonate,triethylamine, DBU, pyridine, DMAP or di-isopropyl ethyl amine was addedinto a solution of agent 2 and acyl chloride in an appropriate solventselected from dichloromethane, chloroform, benzene, toluene, THF,diethyl ether, dioxane, acetone, N,N-dimethylformamide or pyridine atroom temperature. The reaction was carried out at either roomtemperature or experimentally determined optimum temperature up to 150°C. over a period of time (30 minutes to 16 hours) to afford compounds 3which may either be compounds of formula I or precursors. Some selectedreferences involving such reactions include a) Indian J. Chem., Sect B1990, 29, 1077; 2) Chem. Sci. 1998, 53, 1216; 3) Chem. Pharm. Bull 1992,40, 1481; 4) Chem. Heterocycl. Compd. 2002, 38, 539.

Alternatively, as shown in Scheme 2, structure 2 can be coupled with anacid 4 using standard amide bond or peptide bond forming couplingreagents. Many reagents for amide bond couplings are known by an organicchemist skilled in the art and nearly all of these are applicable forrealizing coupled amide products. The combination of EDAC andtriethylamine in tetrahydrofuran or BOPCl and diisopropyl ethyl amine inchloroform have been utilized most frequently but DEPBT, or othercoupling reagents such as PyBop could be utilized. Another usefulcoupling condition employs HATU ((a) J. Chem. Soc. Chem. Comm. 1994,201; (b) J. Am. Chem. Soc. 1994, 116, 11580). Additionally, DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, representsanother efficient method to form the amide bond and provide compounds ofFormula I. DEPBT is either purchased from Adrich or prepared accordingto the procedure described in Organic Lett., 1999, 1, 91. Typically aninert solvent such as DMF or THF is used but other aprotic solventscould be used.

The general agent 2 that's use are exemplified in Schemes 1 and 2, areeither commercially available or may be prepared by the general methodsdescribed in the experimental section. A few nonlimiting examples ofeither commercially available or synthesized reagents 2 is listed below:

When X is N in Formula I, it can be also prepared by coupling acylchloride 1 or acid 4 with Boc-protected piperazine under the conditionsdescribed in Scheme 1 and 2, to furnish compound 5. The following wellestablished deprotection of Boc group under acidic conditions wouldprovide piperazine amide 6. TFA and aqueous HCl are the typical acidsused to effect removal of the Boc group, while the most commonly usedsolvents are either ether or dichloromethane. TFA may be employed asboth reagent and solvent in some instances. Other acidic agents such asformic acid and solvents could also be used to effect BOC removal. Theamide 6 could react with halide under S_(N)2, S_(N)Ar and metal-mediatedcross coupling to provide compound 3 (compounds of formula I orprecursors).

For S_(N)2 and S_(N)Ar reaction, in an aprotic (e.g., THF, DMF, DMSO,benzene) or protic solvent (e.g., MeOH, EtOH, PrOH, BuOH), attemperature from room temperature to 150° C., in the absence or presenceof base such as NaH, pyridine, Et₃N, di-Pr₂NEt, Na₂CO₃, K₂CO₃,piperazine amide 6 can react with halide or heteroaryl sulfone 7 to givecompound 3.

For metal-mediated cross coupling, temperature could vary from roomtemperature to 150° C. and solvents prefer to be aprotic solvents suchas THF, dioxane, DME, DMF and DMSO. Bases can be selected from NaH, KH,pyridine, Et₃N, di-Pr₂NEt, Na₂CO₃, K₂CO₃, NaHMDS, LiHMDS, KHMDS, Na₃PO₄,Na₂HPO₄ and NaH₂PO₄. Pd, Rh, Ru, Ni or Pt agents can be utilized ascatalysts.

EXAMPLES

The following examples illustrate typical syntheses of the compounds ofFormula I as described generally above. These examples are illustrativeonly and are not intended to limit the disclosure in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

Chemistry

Typical Procedures and Characterization of Selected Examples:

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker DPX-300B or VarianGemini 300 at 300 MHz as stated). The chemical shifts were reported inppm on the δ scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30), and DMSO-d6 (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

The preparation of templates A-CO—CO—Cl and A-CO—CO—OH unlessspecifically noted has been described in detail in U.S. Pat. No.6,469,006B1, U.S. Pat. No. 6,573,262B2, U.S. Pat. No. 6,900,323B2,US20050090522A1, U.S. Pat. No. 6,825,201, US20050261296A1,US20040186292A1, US20050267130A1, U.S. Pat. No. 6,900,206B2,US20040063746, WO-00076521, WO-00162255, WO-00204440, WO-02062423,WO-02085301, WO-03068221 or US-2004/0063744. More specifically, thepreparation of 7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridine,2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid,2-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid, 2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid, and2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid were prepared as described in US20050090522A1.

Example Chemistry Section A

The following general methods apply to Example Chemistry Section A:

LC/MS Methods (i.e., Compound Identification)

-   Column A: Xterra MS C18 5 um 4.6×30 mm column-   Column B: Phenomenex 5 u C18 4.6×30 mm column-   Column C: Xterra MS C18 4.6×30 mm column-   Column D: Phenomenex 4.6×50 mm C18 5 um column-   Column E: Xterra 4.6×30 mm S5 column-   Column F: Phenomenex-Luna 4.6×50 mm S10 column-   Column G: Phenomenex 10 u 3.0×50 mm column-   Column H: Phenomenex-Luna 4.6×30 mm S5 column-   Column I: Phenomenex 4.6×30 mm 10 u column-   Column J: Phenomenex C18 10 u 3.0×50 mm column-   Column K: Phenomenex, Onyx Monolithic C18 50×4.6 mm column-   Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B-   Gradient time All the LC-MS, except which are specified otherwise,    use 2 minutes of gradient time.-   Hold time: 1 minute-   Flow rate: a. 5 ml/min    -   b. 4 ml/min-   (All the LC-MS, except which are specified using flow rate b, were    obtained by using flow rate a.)-   Detector Wavelength: 220 nm    Solvent System I-   Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid-   Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid    Solvent System II-   Solvent A: 5% MeCN/95% H₂O/10 mm ammonium acetate-   Solvent B: 95% MeCN/5% H₂O/10 mm ammonium acetate-   (All the LC-MS in the following sections, except which are specified    using solvent system II, were obtained by using solvent system I.)

Compounds purified by preparative HPLC were diluted in methanol (1.2 ml)and purified using the following methods on a Shimadzu LC-10A automatedpreparative HPLC system.

Preparative HPLC Method (i.e., Compound Purification)

Purification Method Initial gradient (40% B, 60% A) ramp to finalgradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100% B, 0%A)

Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid

Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid

Column: YMC C18 S5 20×100 mm column

Detector Wavelength: 220 nm

Typical Procedures and Characterization of Selected Examples:

Preparation of Agent 2

An excess of piperazine (5-10 eq.) was added to a solution ofelectrophile in THF, dioxane or DMF. The reaction was stirred for 17hours at room temperature or 115° C., then was quenched with saturatedaqueous NaHCO₃. The aqueous phase was extracted with EtOAc. The combinedorganic layer was washed with water and dried over MgSO₄, filtered, andthe filtrate concentrated to a residue, which was used in the furtherreactions without purification, or purified by silica gel columnchromatography or Shimadzu automated preparative HPLC System.

An excess of base (1-20 eq., such as Et₃N, iPr₂NEt or NaH), was added toa solution of N-Boc piperazine (2-5 eq.) in THF, dioxane or DMF,followed by addition of electrophile (1 eq.). The reaction was stirredfor 17 hours at room temperature or 115° C., then was quenched withsaturated aqueous NaHCO₃. The aqueous phase was extracted with EtOAc.The combined organic layer was dried over MgSO₄, filtered, and thefiltrate concentrated to a residue, which was used in the furtherreactions without purification, or purified by silica gel columnchromatography or Shimadzu automated preparative HPLC System.

N-Boc piperazine derivative was dissolved in an acidic solution of TFAor HCl in CH₂Cl₂, ether, dioxane or alcohol. After 0.5 to 17 hours, thesolution was concentrated under vacuum to give an salt residue, whichwas partitioned between aqueous NaHCO₃ and EtOAc. The aqueous phase wasextracted with EtOAc. The combined organic layer was dried over MgSO₄,filtered, and the filtrate concentrated to a residue, which was used inthe further reactions without purification, or purified by silica gelcolumn chromatography or Shimadzu automated preparative HPLC System.

To a stirred solution of piperazine (2 eq.) in dry THF was added n-BuLi(2 to 4 eq.) in THF at room temperature. After stirring for 0.5 hour atroom temperature, aryl halide (1 eq.) was added to the solution of anionand the reaction mixture was stirred for an additional 1 to 17 hours atroom temperature to 115° C. The reaction mixture was quenched with MeOH,and the solvents evaporated. The residue was partitioned between EtOAcand sat. NaHCO₃. The aqueous layer was extracted with EtOAc. The organiclayer was dried over MgSO₄ and concentrated to afford the crude product,which was purified by silica gel column chromatography or Shimadzuautomated preparative HPLC System.

To a solution of methyl thio derivative (1 eq.) in dry CH₂Cl₂ or HOAcwas added mCPBA (2-5 eq.) at room temperature. After stirring for 17hours at room temperature, the reaction mixture was quenched withNaHSO₃, and the solvents evaporated. The residue was partitioned betweenEtOAc and sat. NaHCO₃. The aqueous layer was extracted with EtOAc. Theorganic layer was dried over MgSO₄ and concentrated to afford the crudeproduct, which was purified by silica gel column chromatography orShimadzu automated preparative HPLC System.

An excess of piperazine (5-10 eq.) was added to a solution of sulfone orsulfoxide derivative in 1-butanol or 1-pentanol. The reaction wasrefluxed for 17 hours. After cooling down, the reaction was quenchedwith saturated aqueous NaHCO₃. The aqueous phase was extracted withEtOAc. The combined organic layer was washed with water and dried overMgSO₄, filtered, and the filtrate concentrated to a residue, which wasused in the further reactions without purification, or purified bysilica gel column chromatography or Shimadzu automated preparative HPLCSystem.

To a solution of alcohol derivative (1 eq.) in dry pyridine was addedTs-Cl (1-2 eq.) at room temperature. After stirring for 17 hours at roomtemperature, the solvents were evaporated. The residue was partitionedbetween EtOAc and sat. NaHCO₃. The aqueous layer was extracted withEtOAc. The organic layer was dried over MgSO₄ and concentrated to affordthe crude product, which was purified by silica gel columnchromatography or Shimadzu automated preparative HPLC System.

A mixture of an excess of piperazine (5-10 eq.) and tosylate (1 eq.) insealed tube was heated at 115° C. to 170° C. for 1 to 17 hours. Aftercooling down, the reaction was quenched with saturated aqueous NaHCO₃.The aqueous phase was extracted with EtOAc. The combined organic layerwas washed with water and dried over MgSO₄, filtered, and the filtrateconcentrated to a residue, which was used in the further reactionswithout purification, or purified by silica gel column chromatography orShimadzu automated preparative HPLC System.

To a solution of dihalide derivative (1 eq.) in dry THF or dioxane orDMF was added amine (1-1.5 eq.) alone or alcohol (1-1.5 eq.) with NaH(1-5 eq.) at room temperature. After stirring for 17 hours at roomtemperature or 115° C., piperazine derivative (1-5 eq.) was added andthe resulting mixture was heated up to 115° C. for 1 hour to 1 week.Then, the solvents were evaporated. The residue was partitioned betweenEtOAc and sat. NaHCO₃. The aqueous layer was extracted with EtOAc. Theorganic layer was washed with water, dried over MgSO₄ and concentratedto afford the crude product, which was purified by silica gel columnchromatography or Shimadzu automated preparative HPLC System.

To a solution of N-Boc piperidine derivative (1 eq.) and a nucleophilesuch as an amine (1-5 eq.) in dry THF or dioxane or DMF was addediPr₂Net (1-10 eq.) in a sealed tube. The reaction was heated to 115° C.to 170° C. for 1-17 hours before cooling down. Then, the reactionmixture was quenched with NaHCO₃. The aqueous layer was extracted withEtOAc. The organic layer was dried over MgSO₄ and concentrated to affordthe crude product, which was purified by silica gel columnchromatography or Shimadzu automated preparative HPLC System.

N-Boc piperidine derivative was dissolved in an acidic solution of TFAor HCl in CH₂Cl₂, ether, dioxane or alcohol. After 0.5 to 17 hours, thesolution was concentrated under vacuum to give an salt residue, whichwas partitioned between aqueous NaHCO₃ and EtOAc. The aqueous phase wasextracted with EtOAc. The combined organic layer was dried over MgSO₄,filtered, and the filtrate concentrated to a residue, which was used inthe further reactions without purification, or purified by silica gelcolumn chromatography or Shimadzu automated preparative HPLC System.

To a solution of piperidine or piperazine amine derivative (1-2 eq.) anda unsaturated ester (1 eq.) in dry THF or dioxane was added NaOMe (1-10eq.). The reaction was stirred at room temperature or 120° C. for 1-17hours. The solvents were removed under vacuum and the residue waspartioned between NaHCO₃ and EtOAc. The aqueous layer was extracted withEtOAc. The organic layer was dried over MgSO₄ and concentrated to affordthe crude lactam product, which was purified by silica gel columnchromatography or Shimadzu automated preparative HPLC System.

LiAlH₄ (1-5 eq.) was added into a solution of lactam derivative (1 eq.)in dry THF at 0° C. The reaction was stirred at room temperature for 17hours before being quenched by MeOH. The solvents were removed undervacuum and the residue was partioned between NaHCO₃ and EtOAc. Theaqueous layer was extracted with EtOAc. The organic layer was dried overMgSO₄ and concentrated to afford the crude lactam product, which waspurified by silica gel column chromatography or Shimadzu automatedpreparative HPLC System.

At room temperature, MeI (1-5 eq.) was added into a solution of thioderivative (1 eq.) with KOH (5-10 eq.) in water or with NaH (5-10 eq.)in THF, dioxane or DMF. The reaction was stirred at room temperature for1 to 17 hours. The solvents were removed under vacuum and the residuewas partioned between NaHCO₃ and EtOAc. The aqueous layer was extractedwith EtOAc. The organic layer was dried over MgSO₄ and concentrated toafford the crude methyl thio product, which was purified by silica gelcolumn chromatography or Shimadzu automated preparative HPLC System.

To a solution of methyl thio derivative (1 eq.) in dry CH₂Cl₂ or HOAcwas added mCPBA (2-5 eq.) at room temperature. After stirring for 17hours at room temperature, the reaction mixture was quenched withNaHSO₃, and the solvents evaporated. The residue was partitioned betweenEtOAc and sat. NaHCO₃. The aqueous layer was extracted with EtOAc. Theorganic layer was dried over MgSO₄ and concentrated to afford the crudeproduct(s), sulfone or/and sulfoxide derivative, which was purified bysilica gel column chromatography or Shimadzu automated preparative HPLCSystem.

Sulfone or sulfoxide derivative (1 eq.) was added into the THF solutionof piperazine anion (5-10 eq.) which was prepared from piperazine andBuLi (eq. of BuLi/eq. of piperazine=1 to 2) at room temperature in dryTHF. The reaction was stirred at room temperature or refluxed for 17hours. After cooling down, the reaction was quenched with saturatedaqueous NaHCO₃. The aqueous phase was extracted with EtOAc. The combinedorganic layer was washed with water and dried over MgSO₄, filtered, andthe filtrate concentrated to a residue, which was used in the furtherreactions without purification, or purified by silica gel columnchromatography or Shimadzu automated preparative HPLC System.

Hydroxyl or thio derivative (1 eq.) was added into the POCl₃ or POBr₃with or without DMF. The reaction was heated to 100° C. to 170° C. for 1to 17 hours. After cooling down, the reaction was quenched withsaturated aqueous NaHCO₃. The aqueous phase was extracted with EtOAc.The combined organic layer was washed with water and dried over MgSO₄,filtered, and the filtrate concentrated to a residue, which was used inthe further reactions without purification, or purified by silica gelcolumn chromatography or Shimadzu automated preparative HPLC System.

A mixture of an excess of piperazine (5-10 eq.) and halide (1 eq.) inBuOH, PnOH, THF, dioxane or DMF was stirred at room temperature orheated at 170° C. for 1 to 17 hours. Cu or Pd catalyst may be utilized.The reaction was quenched with saturated aqueous NaHCO₃. The aqueousphase was extracted with EtOAc. The combined organic layer was washedwith water and dried over MgSO₄, filtered, and the filtrate concentratedto a residue, which was used in the further reactions withoutpurification, or purified by silica gel column chromatography orShimadzu automated preparative HPLC System.

TABLE A-1 MS MS (M + H)⁺ Inter- (M + Observ. And me- Method StartingComercially Available H)⁺ Retention Time diate Structure Used MaterialsCalcd. and NMR I-01

A

231.14 231.21 Rf = 0.83 min (column H, flow rate b) I-02

A

245.15 245.38 Rf = 0.83 min (column H, flow rate b) I-03

A

245.15 245.39 Rf = 0.83 min (column H, flow rate b) I-04

D

230.14 230.06 Rf = 0.65 min (column F, flow rate b) I-05

A

246.14 246.28 Rf = 0.32 min (column H, flow rate b) I-06

From commercial supplier I-07

From commercial supplier I-08

A

241.15 241.15 Rf = 0.70 min (column J) ¹H NMR (500 MHz, CD₃OD) δ 8.22(s, 2 H), 7.85 (d, 2 H, J = 10 Hz), 7.51 (m, 3 H), 3.38 (m, 4 H), 3.19(m, 4 H); ¹³C NMR (125 MHz, CD₃OD) δ 156.11, 146.47, 141.52, 139.56,138.06, 130.50, 130.03, 128.88, 46.50, 44.13. I-09

A

247.10 247.20 Rf = 1.98 min (column I) ¹H NMR (500 MHz, CD₃OD) δ 7.96(m, 2 H), 7.54 (m, 3 H), 3.51-3.33 (m, 8H); ¹³C NMR (125 MHz, CD₃OD) δ161.1, 152.1, 133.6, 129.9, 129.1, 127.7, 46.7, 43.0. HRMS: 247.1023(calc. 247.1017) I-10

From commercial supplier I-11

From commercial supplier I-12

A

241.15 241.21 Rf = 1.37 min (column H, flow rate b) I-13

From commercial supplier I-14

A

246.11 246.17 Rf = 1.40 min (column H, flow rate b) I-15

E

245.20 245.34 Rf = 0.92 min (column I) I-16

H

232.14 232.29 Rf = 1.11 min (column H, flow rate b) I-17

H

231.15 231.32 Rf = 1.11 min (column H, flow rate b) I-18

H

217.17 217.30 Rf = 1.07 min (column F, flow rate b) I-19

G

230.18 231.25 Rf = 0.46 min (column I) I-20

A

259.17 259.33 Rf = 1.01 min (column E, flow rate b, gradient time 4 min)I-21

A

259.17 259.36 Rf = 1.04 min (column H, flow rate b) I-22

C

245.20 245.39 Rf = 1.79 min (column H, flow rate b) I-23

From commercial supplier I-24

From commercial supplier I-25

From commercial supplier I-26

From commercial supplier I-27

From commercial supplier I-28

B

245.15 245.29 Rf = 0.99 min (column F, flow rate b) I-29

From commercial supplier I-30

From commercial supplier I-31

From commercial supplier I-32

A

236.14 236.30 Rf = 1.15 min (column H, rate b) I-33

A

291.15 291.31 Rf = 1.22 min (column H, flow rate b) I-34

F

223.16 223.30 Rf = 1.13 min (column H, flow rate b) I-35

F

248.19 248.34 Rf = 1.16 min (column H, flow rate b) I-36

F

249.18 249.33 Rf = 0.37 min (column H, flow rate b) I-37

A

309.18 309.37 Rf = 1.53 min (column H, flow rate b) I-38

A

275.19 275.36 Rf = 1.09 min (column H, flow rate b) I-39

A

291.18 291.37 Rf = 0.76 (column H, flow rate b) I-40

A

243.16 243.33 Rf = 1.30 min (column H, flow rate b) I-41

A

285.17 285.36 Rf = 1.25 min (column H, flow rate b) I-42

A

261.12 261.29 Rf = 1.18 min (column H, flow rate b) I-43

A

225.18 225.32 Rf = 0.87 min (column H, flow rate b) I-44

J

244.16 244.33 Rf = 0.65 min (column F, flow rate b) I-45

I

279.16 279.19 Rf = 0.88 min (column F, flow rate b) I-46

C

243.16 243.36 Rf = 0.96 min (column F, flow rate b) I-47

I

229.15 229.30 Rf = 0.28 min (column F, flow rate b) I-48

F

209.14 209.18 Rf = 1.06 min (column H, flow rate b) I-49

A

189.11 189.13 Rf = 0.63 (column H, flow rate b) I-50

A

269.14 269.32 Rf = 0.86 (column H, flow rate b) I-51

A

275.10 275.28 Rf = 0.98 (column H, flow rate b) I-52

A

205.03 205.20 Rf = 1.68 (column H, flow rate b) I-53

J

245.18 245.19 Rf = 0.69 (column F, flow rate b) I-54

B

245.15 245.29 Rf = 0.99 min (column F, flow rate b) I-55

A

274.10 273.98 Rf = 1.18 (column H, flow rate b) I-56

A

258.12 258.02 Rf = 0.96 (column H, flow rate b) I-57

A

288.12 287.98 Rf = 1.27 (column H, flow rate b) I-58

A

254.14 254.41 Rf = 1.56 (column H, flow rate b) I-59

A

240.13 240.40 Rf = 1.33 (column H, flow rate b) I-60

A

256.12 256.39 Rf = 1.10 (column H, flow rate b) I-61

A

311.13 311.30 Rf = 1.14 (column H, flow rate b) I-62

A

325.15 325.32 Rf = 1.49 (column H, flow rate b) I-63

A

279.15 279.31 Rf = 0.61 (column H, flow rate b) I-64

A

289.20 289.37 Rf = 1.16 (column H, flow rate b) I-65

A

297.17 297.34 Rf = 1.05 (column H, flow rate b) I-66

A

283.16 283.33 Rf = 1.13 (column H, flow rate b) I-67

A

292.21 292.42 Rf = 0.28 (column H, flow rate b) I-68

A

293.16 293.45 Rf = 0.57 (column H, flow rate b) I-69

A

352.21 352.24 Rf = 1.31 (column H, flow rate b) I-70

A

288.15 288.39 Rf = 1.03 (column H, flow rate b) I-71

A

307.16 307.43 Rf = 1.22 (column H, flow rate b) I-72

A

245.14 245.38 Rf = 0.67 (column H, flow rate b) I-73

A

259.16 259.41 Rf = 0.83 (column H, flow rate b) I-74

A

273.17 273.42 Rf = 0.94 (column H, flow rate b) I-75

A

287.19 287.44 Rf = 1.11 (column H, flow rate b) I-76

A

301.20 301.46 Rf = 1.25 (column H, flow rate b) I-77

A

292.17 292.46 Rf = 1.13 (column H, flow rate b) I-78

A

306.18 306.46 Rf = 1.26 (column H, flow rate b) I-79

A

320.20 320.48 Rf = 1.36 (column H, flow rate b) I-80

A

334.21 334.50 Rf = 1.48 (column H, flow rate b) I-81

A

348.23 348.50 Rf = 1.61 (column H, flow rate b) I-82

A

297.12 297.30 Rf = 1.49 (column H, flow rate b) I-83

A

206.13 206.29 Rf = 0.58 (column H, flow rate b) I-84

A

192.11 301.46 Rf = 1.25 (column H, flow rate b) I-85

A

277.17 277.34 Rf = 0.63 (column H, flow rate b) I-86

A

257.15 257.21 Rf = 1.05 min (column E, flow rate b, gradient time 4 min)I-87

B

257.15 257.18 Rf = 0.97 min (column E, flow rate b, gradient time 4 min)I-88

A

245.15 245.15 Rf = 0.83 min (column E, flow rate b, gradient time 4 min)I-89

A

243.14 243.29 Rf = 0.92 min (column E, flow rate b, gradient time 4 min)

Preparation of Compound 3

Et₃N or iPr₂NEt (1-100 eq.) was added into a solution of 2-keto acylchloride (1 eq.) and piperazine or piperidine derivative (1-5 eq.) in anaprotic solvent (such as THF, DMF, dioxane, ether, acetonitrile) andreaction was stirred at room temperature or 50° C. or 80° C. or 115° C.for 17 hours before quenched with saturated aqueous NaHCO₃ solution. Theaqueous layer was extracted with ethyl acetate. The organic phasecombined and dried over anhydrous MgSO₄. Concentration in vacuo provideda crude product, which was purified by tritaration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC System.

2-Keto acid (1 eq.), piperazine (1-5 eq.),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) orO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1-5 eq.) and Hunig's Base or N-methyl morpholine (1-100 eq.)were combined in THF or DMF. The mixture was stirred at room temperaturefor 17 hours. THF or DMF was removed via evaporation at reduced pressureand the residue was partitioned between ethyl acetate and 5-10% Na₂CO₃aqueous solution. The aqueous layer was extracted with ethyl acetate.The organic phase combined and dried over anhydrous MgSO₄. Concentrationin vacuo provided a crude product, which was purified by tritaration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC System.

Et₃N or iPr₂NEt (1-100 eq.) was added into a solution of 2-keto acylchloride (1 eq.) and Boc-piperazine (1-5 eq.) in an aprotic solvent(such as THF, DMF, dioxane, ether, acetonitrile) and reaction wasstirred at room temperature or 50° C. or 80° C. or 115° C. for 17 hoursbefore quenched with saturated aqueous NaHCO₃ solution. The aqueouslayer was extracted with ethyl acetate. The organic phase combined anddried over anhydrous MgSO₄. Concentration in vacuo provided a crudeproduct, which was purified by tritaration, or recrystallization, orsilica gel column chromatography, or Shimadzu automated preparative HPLCSystem.

N-Boc piperazine keto amide derivative was dissolved in an acidicsolution of TFA or HCl in CH₂Cl₂, ether, dioxane or alcohol. After 0.5to 17 hours, the solution was concentrated under vacuum to give an saltresidue, which was used in the next step without purification. Or, saltprecipitated out from solution, which was washed with CH₂Cl₂, ether,dioxane or alcohol before further use.

An excess of base (1-20 eq., such as Et₃N, iPr₂NEt or NaH), was added toa solution of 2-keto acyl piperazine (1 eq.) in THF or DMF, followed byaddition of electrophile (1 to 10 eq.). The reaction was stirred for 17hours at room temperature or 115° C., then was quenched with saturatedaqueous NaHCO₃. The aqueous phase was extracted with EtOAc. The combinedorganic layer was dried over MgSO₄, filtered, and the filtrateconcentrated to a residue, which was used in the further reactionswithout purification, or purified by silica gel column chromatography orShimadzu automated preparative HPLC System.

2-Keto acid (1 eq.), N-Boc piperazine (1-5 eq.),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) orO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in THF orDMF. The mixture was stirred at room temperature for 17 hours. THF orDMF was removed via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ aqueous solution. Theaqueous layer was extracted with ethyl acetate. The organic phasecombined and dried over anhydrous MgSO₄. Concentration in vacuo provideda crude product, which was purified by tritaration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC System.

N-Boc piperazine keto amide derivative was dissolved in an acidicsolution of TFA or HCl in CH₂Cl₂, ether, dioxane or alcohol. After 0.5to 17 hours, the solution was concentrated under vacuum to give an saltresidue, which was used in the next step without purification. Or, saltprecipitated out from solution, which was washed with CH₂Cl₂, ether,dioxane or alcohol before further use.

An excess of base (1-20 eq., such as Et₃N, iPr₂NEt or NaH), was added toa solution of 2-keto acyl piperazine (1 eq.) in THF or DMF, followed byaddition of electrophile (1 to 10 eq.). The reaction was stirred for 17hours at room temperature or 115° C., then was quenched with saturatedaqueous NaHCO₃. The aqueous phase was extracted with EtOAc. The combinedorganic layer was dried over MgSO₄, filtered, and the filtrateconcentrated to a residue, which was used in the further reactionswithout purification, or purified by silica gel column chromatography orShimadzu automated preparative HPLC System.

To a sealed tube, azaindole or indole halide (bromide or chloride),boron or stannane agent (1-20 eq.), Pd catalyst (including but notlimited to Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, Pd(OAc)₂, Pd₂(dba)₃, PdCl₂(dppf)₂,0.05-2 eq.), base (including but not limited to Na₂CO₃, K₂CO₃, Cs₂CO₃,Na₂HPO₃, NaH₂PO₃, Na₃PO₄, NaOAc, NaOEt, NaOtBu, Et₃N, iPr₂NEt, NaH,K₂HPO₃, KH₂PO₃, K₃PO₄, KOAc, KOEt, KOtBu, 1-20 eq.) were combined indioxane, toluene or DMF in the presence of or in the absence of water,with or without using a ligand (including but not limited to BINOL,BINAP, 2,2′-bipyridyl, tri-alkylphosphine, dppe, dppf, AsPh₃, 1-2 eq.).The reaction was heated at 50-170° C. for 2-17 h. After the mixturecooled down to rt, it was poured into water. The solution was extractedwith EtOAc or dichloromethane. The combined extract was concentrated togive a residue which was purified by silica gel column chromatography orShimadzu automated preparative HPLC System.

TABLE A-2 MS MS (M + H)⁺ Compd Method (M + H)⁺ Observ. And Retention #Structure Used Calcd. Time and NMR A-1

D 500.19 500.18 Rf = 1.78 min (column F, flow rate b) A-2

B 496.19 495.95 Rf = 2.30 min (column F, flow rate b) HRMS: 496.1917(calc. 496.1897) A-3

B 496.19 495.96 Rf = 2.24 min (column F, flow rate b) HRMS: 496.1909(calc. 496.1897) A-4

B 496.19 495.96 Rf = 2.40 min (column F, flow rate b) HRMS: 496.1917(calc. 496.1897) A-5

B 488.17 488.17 Rf = 1.56 min (column I) ¹H NMR (500 MHz, DMSO-d₆) δ9.00(s, 1H), 8.36 (s, 1H), 8.31 (d, 1H, J = 2 Hz), 8.1 (d,, 1H, J = 1.5 Hz),7.64 (m, 5H), 3.72 (m, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 3.18 (m, 2H);¹³C NMR (125 MHz, DMSO- d₆) δ183.9, 165.4, 156.9, 153.2, 151.1, 141.6,134.3, 134.0, 131.4, 130.0, 125.8, 124.3, 122.9, 121.9, 121.8, 113.0,48.1, 47.5, 44.3. HRMS: 488.1725 (calc. 488.1707) A-6

B 514.18 514.20 Rf = 1.61 min (column I) ¹H NMR (500 MHz, DMSO-d₆) δ8.98(s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.69 (m, 2H), 7.43(m, 3H), 6.16 (s, 1H), 3.60-2.83 (m, 8H); ¹³C NMR (125 MHz, DMSO- d₆)δ183.9, 165.3, 161.4, 152.9, 151.1, 141.8, 141.4, 136.1, 133.9, 131.4,128.6, 128.4, 127.6, 125.9, 125.7, 122.8, 113.0, 110.2, 49.1, 48.5,44.4. HRMS: 514.1765 (calc. 514.1751) A-7

B 498.18 498.23 Rf = 1.81 min (column I) HRMS: 498.1818 (calc. 498.1802)A-8

B 503.14 502.89 Rf = 2.13 min (column F, flow rate b) ¹H NMR (500 MHz,DMSO-d₆) δ9.01 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.86(m, 2H), 7.39 (m, 4H), 3.84-3.52 (m, 8H), 2.45 (s, 3H); ¹³C NMR (125MHz, DMSO-d₆) δ183.8, 170.0, 165.4, 153.1, 151.1, 150.5, 141.3, 134.4,133.9, 131.3, 128.3, 127.4, 125.6, 122.7, 121.8, 121.7, 113.0, 102.9,48.0, 47.4, 44.5. HRMS: 503.1401 (calc. 503.1414) A-9

B 513.20 513.96 Rf = 1.78 min (column F, flow rate b) ¹H NMR (500 MHz,DMSO-d₆) δ9.22 (s, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.64 (m, 5H), 3.98(s, 3H), 3.71-3.17 (m, 8H), 2.45 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆)δ185.3, 166.2, 161.3, 156.9, 149.2, 142.1, 138.6, 134.3, 123.0, 129.9,129.6, 124.3, 123.7, 122.8, 121.2, 114.1, 56.8, 47.9, 47.6, 44.2, 13.7.HRMS: 514.2039 (calc. 514.2064) A-10

B 403.16 403.11 Rf = 1.60 min (column F, flow rate b) ¹H NMR (500 MHz,DMSO-d₆) δ8.47 (m, 3H), 7.63 (m, 5H), 7.31 (m, 1H), 3.91-3.15 (m, 8H);¹³C NMR (125 MHz, DMSO- d₆) δ185.7, 165.4, 156.9, 149.1, 144.8, 137.4,134.3, 129.9, 129.8, 129.3, 124.3, 118.6, 117.3, 111.7, 48.1, 47.5,44.3. HRMS: 403.1651 (calc. 433.1631) A-11

B 433.17 433.19 Rf = 1.33 min (column F, flow rate b) ¹H NMR (500 MHz,DMSO-d₆) δ8.23 (d, 1H, J = 5.5 Hz), 8.18 (s, 1H), 7.63 (m, 5H), 6.87 (d,1H, J = 5.5 Hz), 3.92 (s, 3H), 3.67- 3.15 (m, 8H); ¹³C NMR (125 MHz,DMSO-d₆) δ185.0, 166.6, 160.2, 156.9, 151.1, 146.7, 135.3, 134.3, 129.9,129.8, 124.3, 112.5, 106.3, 100.8, 55.7, 48.0, 47.5, 44.2, 40.2. HRMS:433.1752 (calc. 433.1737) A-12

B 463.18 463.22 Rf = 1.55 min (column F, flow rate b) ¹H NMR (500 MHz,DMSO-d₆) δ8.15 (s, 1H, 7.64 (m, 5H), 7.47 (m, 1H), 4.02 (s, 3H), 3.83(s, 3H), 3.66 (m, 2H), 3.39 (m, 2H), 3.31 (m, 2H), 3.17 (m, 2H); ¹³C NMR(125 MHz, DMSO-d₆) δ185.4, 166.5, 156.9, 146.3, 145.8, 136.5, 134.3,129.9, 129.8, 124.3, 122.4, 122.2, 119.6, 114.4, 57.0, 52.9, 47.9, 47.5,44.2. HRMS: 463.1853 (calc. 463.1842) A-13

B 504.14 504.17 Rf = 2.23 min (column F, flow rate b) ¹H NMR (500 MHz,DMSO-d₆) δ9.01 (s, 1H), 8.36 (s, 1H), 8.31 (d, 1H, J = 2 Hz), 8.1 (d,,1H, J = 1 Hz), 7.91-7.50 (m, 5H), 3.78 (m, 2H), 3.55 (m, 2H), 3.27 (m,2H), 3.14 (m, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ183.9, 165.4, 161.3,153.1, 151.1, 141.2, 133.8, 132.9, 131.3, 129.5, 128.7, 127.2, 125.9,125.6, 122.7, 121.7, 113.0, 49.2, 48.7, 44.6. HRMS: 504.1370 (calc.504.1366) A-14

B 502.19 502.20 Rf = 1.80 min (column F, flow rate b) HRMS: 502.1874(calc. 502.1864) A-15

B 502.19 502.22 Rf = 1.88 min (column F, flow rate b) HRMS: 502.1874(calc. 502.1864) A-16

B 535.20 535.28 Rf = 1.57 min (column F, flow rate b) HRMS: 535.1990(calc. 535.2006) A-17

B 498.18 498.20 Rf = 2.02 min (column F, flow rate b) ¹H NMR (500 MHz,DMSO-d₆) δ9.05 (s, 1H), 8.37-7.42 (m, 10H), 3.67 (m, 2H), 3.44 (m, 2H),3.24 (m, 2H), 3.11 (m, 2H) A-18

B 488.22 488.22 Rf = 1.54 min (column F, flow rate b) A-19

B 502.24 502.24 Rf = 1.68 min (column F, flow rate b) A-20

B 487.18 487.30 Rf = 1.60 min (column F, flow rate b) A-21

B 488.18 488.30 Rf = 2.08 min (column F, flow rate b) A-22

B 503.17 503.28 Rf = 1.75 min (column F, flow rate b) A-23

B 489.18 489.32 Rf = 1.98 min (column F, flow rate b) A-24

B 474.21 474.37 Rf = 1.72 min (column F, flow rate b) A-25

A 478.16 478.11 Rf = 1.82 min (column F, flow rate b) A-26

B 516.20 516.24 Rf = 1.84 min (column F, flow rate b) A-27

A 420.16 420.30 Rf = 1.62 min (column H, flow rate b) A-28

B 504.14 503.87 Rf = 2.19 min (column F, flow rate b) A-29

B 498.18 498.20 Rf = 2.02 min (column F, flow rate b) A-30

B 528.22 528.27 Rf = 1.73 min (column F, flow rate b) A-31

B 528.22 528.27 Rf = 1.71 min (column F, flow rate b) A-32

B 542.24 542.28 Rf = 1.77 min (column F, flow rate b) A-33

B 487.16 487.02 Rf = 1.46 min (column K, flow rate 3 ml/min, solvent A =water, solvent B = acetonitrile, modifier = 10 mM NH₄OAC, start %solvent B = 10%, final % solvent B = 95%) A-34

B 488.16 488.00 Rf = 1.37 min (column K, flow rate 3 ml/min, solvent A =water, solvent B = acetonitrile, modifier = 10 mM NH₄OAC, start %solvent B = 10%, final % solvent B = 95%) A-35

B 528.19 528.06 Rf = 1.87 min (column K, flow rate 3 ml/min, solvent A =water, solvent B = acetonitrile, modifier = 10 mM NH₄OAC, start %solvent B = 10%, final % solvent B = 95%) A-36

B 534.21 534.13 Rf = 2.00 min (column K, flow rate 3 ml/min, solvent A =water, solvent B = acetonitrile, modifier = 10 mM NH₄OAC, start %solvent B = 10%, final % solvent B = 95%) A-37

B 536.20 536.41 Rf = 1.66 min (column F, flow rate b) A-38

B 562.23 562.42 Rf = 1.62 min (column F, flow rate b) A-39

B 528.25 528.21 Rf = 3.00 min (column H, flow rate b, gradient time 4min, start % solvent B = 20%, final % solvent B = 60%) A-40

B 502.21 502.30 Rf = 1.57 min (column F, flow rate b) A-41

B 502.24 502.31 Rf = 2.46 min (column F, flow rate b) A-42

B 502.24 502.33 Rf = 2.57 min (column F, flow rate b) A-43

B 485.18 485.33 Rf = 1.47 min (column F, flow rate b) A-44

B 513.21 513.31 Rf = 1.53 min (column F, flow rate b) ¹H, NMR (500 MHz,CDCl₃) δ10.94 (s, 1H), 9.25 (s, 1H), 8.30 (d, 1H), 8.20 (d, 1H), 7.76(s, 1H), 7.61 (m, 3H), 7.50 (d, 2H), 4.03 (s, 3H), 3.79 (m, 2H), 3.56(m, 2H), 3.38 (m, 2H), 3.31 (m, 2H), 2.60 (s, 3H). A-45

B 502.19 502.33 Rf = 1.88 min (column F, flow rate b) A-46

B 528.22 528.37 Rf = 1.88 min (column F, flow rate b) A-47

B 501.19 501.31 Rf = 1.53 min (column F, flow rate b) A-48

B 500.20 500.35 Rf = 1.97 min (column F, flow rate b) A-49

B 486.18 486.23 Rf = 1.52 min (column F, flow rate b) A-50

B 464.18 464.05 Rf = 1.68 min (column K, flow rate 3 ml/min, solvent A =water, solvent B = acetonitrile, modifier = 10 mM NH₄OAC, start %solvent B = 10%, final % solvent B = 95%) A-51

B 489.14 489.00 Rf = 1.77 min (column K, flow rate 3 ml/min, solvent A =water, solvent B = acetonitrile, modifier = 10 mM NH₄OAC, start %solvent B = 10%, final % solvent B = 95%) A-52

B 488.15 488.00 Rf = 2.02 min (column K, flow rate 3 ml/min, solvent A =water, solvent B = acetonitrile, modifier = 10 mM NH₄OAC, start %solvent B = 10%, final % solvent B = 95%) A-53

B 511.35 511.94 Rf = 1.53 (Column F, Flow rate b) A-54

A 512.55 512.34 Rf = 1.41 (Column F, Flow rate b) A-55

A 536.52 536.23 Rf = 1.77 min (Column F, Flow rate b) A-56

B 467.89 467.55 Rf = 2.63 (Column F, Flow rate a) A-57

E 510.53 509.96 Rf = 1.51 (Column F, Flow rate b) A-58

B 528.55 528.18 Rf = 1.75 (Column F, Flow rate b) A-59

B 501.48 501.14 Rf = 1.47 (Column F, Flow rate b) ¹H NMR (500 MHz,CDCl₃) δ11.35 (s, 1H), 8.71 (s, 1H) 8.60 (s, 1H), 8.25 (d, 1H), 7.88 (m,1H), 7.83 (m, 3H), 7.45 (m, 1H), 4.07 (s, 3H), 3.90 (m, 2H), 3.66 (m,2H), 3.58 (m, 2H), 3.51 (m, 2H). A-60

B 528.22 528.53 Rf = 1.84 min (column F, flow rate b) HRMS: 528.2233(calc. 528.2220) ¹H NMR (500 MHz, CDCl₃) δ11.06 (s, 1H), 9.05 (s, 1H),8.16-8.13 (d & d, 1H, J = 3.05, 3.05 Hz), 7.69 (s, 1H), 7.60-7.50 (m,5H), 4.34- 4.09 (m, 1H), 4.00 (d, 3H, J = 2.14 Hz), 3.88-3.65 (m, 2H),3.53-3.28 (m, 4H), 2.52 (s, 3H) 1.27-1.18 (d & d, 3H, J = 6.72, 6.72Hz). A-61

B 502.19 502.50 Rf = 1.88 min (column F, flow rate b) HRMS: 502.1873(calc. 502.1864) ¹H NMR (500 MHz, DMSO- D₆) δ13.03 (s, 1H), 8.99 (d, 1H,J = 4.88 Hz), 8.41- 8.23 (m, 2H), 8.01 (s, 1H), 7.69-7.57 (m, 5H), 4.08(m, 1H), 3.80-3.69 (m, 2H), 3.40-3.20 (m, 4H), 1.15-1.01 (d & d, 3H, J =6.72, 6.71 Hz) A-62

B 465.18 465.61 Rf = 1.66 min (column F, flow rate b) HRMS: 465.1817(calc. 465.1799) A-63

B 491.22 491.66 Rf = 2.01 min (column F, flow rate b) HRMS: 491.2145(calc. 491.2155) A-64

B 579.22 579.46 Rf = 1.84 min (column I, flow rate a) A-66

B 560.18 560.11 Rf = 1.40 min (column F, flow rate b) A-67

A 464.12 464.07 Rf = 1.60 min (column F, flow rate b) A-68

B 572.18 571.97 Rf = 1.74 min (column F, flow rate b) ¹H NMR (500 MHz,MeOD) δ9.11 (s, 1H), 8.33 (dd, 1H, J = 4.73, 1.98 Hz), 8.23 (s, 1H),8.07 (dd, 1H, J = 7.78, 1.98 Hz), 8.04 (d, 1H, J = 3.05 Hz), 7.90 (d,1H, J = 3.05 Hz), 7.75 (s, 1H), 6.91 (dd, 1H, J = 7.63, 4.85 Hz), 4.01(s, 3H), 3.74-3.68 (m, 2H), 3.54-3.43 (m, 4H), 3.40-3.36 (m, 2H), 2.88(q, 2H, J = 7.63 Hz), 1.39 (t, 3H, J = 7.63 Hz). A-69

B 529.22 529.01 Rf = 1.53 min (column F, flow rate b) ¹H NMR (500 MHz,MeOD) δ9.10 (s, 1H), 8.59-8.58 (m, 1H), 8.25 (s, 1H), 8.05- 8.01 (m,1H), 7.81 (d, 1H, J = 7.93 Hz), 7.76 (s, 1H), 7.52-7.49 (m, 1H), 4.03(s, 3H), 3.88-3.86 (m, 2H), 3.64-3.59 (m, 2H), 3.55- 3.51 (m, 2H),3.46-3.41 (m, 2H), 2.88 (q, 2H, J = 7.63 Hz), 1.38 (t, 3H, J = 7.63 Hz).A-70

B 528.22 528.01 Rf = 1.57 min (column F, flow rate b) ¹H NMR (500 MHz,MeOD) δ9.11 (s, 1H), 8.24 (s, 1H), 7.76 (s, 1H), 7.61-7.55 (m, 5H), 4.02(s, 3H), 3.84- 3.77 (m, 2H), 3.57-3.52 (m, 2H), 3.43-3.38 (m, 2H),3.29-3.25 (m, 2H), 2.88 (q, 2H, J = 7.63 Hz), 1.38 (t, 3H, J = 7.63 Hz).A-71

B 514.19 514.18 HRMS: 514.1844 (calc. 514.1864) ¹H NMR (500 MHz,DMSO-D₆) δ13.00 (s, 1H), 9.01 (s, 1H) 8.37 (s, 1H), 8.30 (d, J = 2 Hz,1H), 8.11 (d, J = 1 Hz, 1H), 7.68-7.61 (m, 5H), 4.67 (s, 1H), 4.23 (s,1H), 3.33-3.29 (m, 2H), 3.25-3.18 (m, 2H), 1.90- 1.83 (m, 4H). A-72

B 514.19 514.19 Rf = 2.30 min (column E, flow rate b, gradient time 4min) HRMS: 514.1874 (calc. 514.1864) ¹H NMR (300 MHz, DMSO-D6) δ13.01(s, 1H), 8.98 (s, 1H), 8.42-8.27 (m, 2H), 8.11 (s, 1H), 7.62- 7.50 (m,5H), 4.53-4.23 (m, 1H), 4.05-3.87 (m, 2H), 3.70-3.59 (m, 1H), 3.42-3.10(m, 2H), 2.13- 2.10 (m, 1H), 1.98-1.72 (m, 3H). A-73

B 542.24 542.23 HRMS: 516.2366 (calc. 516.2377) ¹H NMR (300 MHz,DMSO-D₆) δ12.36 (s, 1H), 9.23 (s, 1H), 8.19 (s, 1H), 7.87 (s, 1H),7.70-7.62 (m, 5H), 4.59-4.56 (m, 1H), 3.95 (s, 3H), 3.83-3.79 (m, 1H),3.40-3.28 (m, 2H), 3.17-3.12 (dd, J = 12, 4 Hz, 1H), 2.98-2.93 (dd, J =12, 4 Hz, 1H), 2.48 (s, 3H), 1.23- 1.17 (m, 6H). A-74

B 500.17 500.47 HRMS: 500.1707 (calc. 500.1683) ¹H NMR (300 MHz,DMSO-D₆) δ ppm 13.00 (s, 1H), 9.00 (s, 1H), 8.51- 8.44 (m, 1H), 8.28 (d,J = 2 Hz, 1H), 8.12 (s, 1H), 7.64- 7.54 (m, 5H), 4.84-4.49 (m, 2H),3.85-3.55 (m, 2H), 3.26-3.16 (m, 1H), 3.07-2.98 (m, 1H), 2.01- 1.93 (t,J = 12 Hz, 2H)

Example Chemistry Section B

The following general methods apply to Example Chemistry Section B:

LCMS Data:

Method 1

Gradient time: 2 min

Flow rate: 4 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 10% MeOH/90% H₂O with 0.1% TFA

Eluent B: 90% MeOH/10% H₂O with 0.1% TFA

Column: Phenomenex-luna 3.0×50 mm S10

Method 2

Gradient time: 2 min

Flow rate: 5 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 10% MeOH/90% H₂O with 0.1% TFA

Eluent B: 90% MeOH/10% H₂O with 0.1% TFA

Column: Phenomenex-luna 10 u C18 3.0×50 mm

Method 3

Gradient time: 2 min

Flow rate: 5 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 5% ACN/95% H₂O with 10 mm Ammonium Acetate

Eluent B: 95% ACN/5% H₂O with 10 mm Ammonium Acetate

Column: Luna 4.6×50 mm S10

Method 4

Gradient time: 3 min

Flow rate: 4 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 10% MeOH/90% H₂O with 0.1% TFA

Eluent B: 90% MeOH/10% H₂O with 0.1% TFA

Column: Phenomenex-luna 10 u C18 3.0×50 mm

Method 5

Gradient time: 4 min

Flow rate: 4 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 10% MeOH/90% H₂O with 0.1% TFA

Eluent B: 90% MeOH/10% H₂O with 0.1% TFA

Column: Phenomenex-luna 10 u C18 3.0×50 mm

Method 6

Gradient time: 3 min

Flow rate: 4 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 10% MeOH/90% H₂O with 0.1% TFA

Eluent B: 90% MeOH/10% H₂O with 0.1% TFA

Column: Phenomenex-luna 10 u C18 30×4.6 mm

Method 7

Gradient time: 3 min

Flow rate: 4 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 10% MeOH/90% H₂O with 0.1% TFA

Eluent B: 90% MeOH/10% H₂O with 0.1% TFA

Column: Phenomenex-luna 10 u C18 3.0×50 mm

Method 8

Gradient time: 3 min

Flow rate: 4 ml/min

Stop time Gradient time+1 min

Starting conc.: 0% B

Eluent A: 95% water/5% ACN with 10 mm Ammonium Acetate

Eluent B: 5% water/95% ACN with 10 mm Ammonium Acetate

Column: Xterra 3.0×50 mm S7

Method 9

Gradient time: 4 min

Flow rate: 4 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 5% ACN/95% H₂O with 10 mm Ammonium Acetate

Eluent B: 95% ACN/5% H₂O with 10 mm Ammonium Acetate

Column: Luna 4.6×50 mm Phenomenex Luna

Method 10:

LC-MS instrument: WFD-442A-LCMS2, Wavelength=220

Gradient time: 2 min

Flow rate: 4 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 10% MeOH/90% H₂O with 0.1% TFA

Eluent B: 90% MeOH/10% H₂O with 0.1% TFA

Column: Phenomenex-luna 4.6×30 mm S10

Preparation of1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-1)

7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridine (2.0 g, 9.3 mmol) was addedto a mixture of AlCl₃ (7.5 g, 55.8 mmol) and ethylmethylimidazoliumchloride (2.7 g, 18.6 mmol). Methyl chlorooxoacetate (2.1 mL, 18.6 mmol)was added slowly to the above solution and the mixture was stirred atroom temperature for 3 h. Reaction flask was placed in an ice bath andwater was slowly added until a white precipitate formed. The solid wascollected by filtration and washed with water to afford2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.4g, 92%). LCMS: m/e 287 (M+H)⁺, ret time 0.91 min (method 1).

2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (5.0g, 17.5 mmol) was dissolved in DMF (100 mL) and treated with1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.0 g, 17.5 mmol), Hunig's base(9.2 mL, 52.6 mmol) and TBTU (5.6 g, 17.5 mmol) and the reaction mixturewas stirred at rt for 18 h. Solvent was removed in vacuum and water wasadded. A white solid precipitated out and it was collected by filtrationand recrystallized twice with MeOH to afford the title compound (4.58 g)as a white solid. The mother liquid was concentrated and purified usingsilica gel (CH₂Cl₂ to 5% MeOH/CH₂Cl₂) to afford more title compound (1.8g). ¹HNMR (500 MHz, DMSO) δ 8.47 (s, 1H), 8.16 (s, 1H), 7.70-7.59 (m,5H), 3.67 (m, 2H), 3.44 (m, 2H), 3.37 (m, 2H), 3.20 (m, 2H). LCMS: m/e499 (M+H)⁺, ret time 1.50 min (method 1).

Preparation of1-(4-fluoro-7-(3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-2) and1-(4-fluoro-7-(5-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-3)

A mixture of1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(50 mg, 0.1 mmol), potassium carbonate (13 mg, 0.1 mmol), copper (6.0mg, 0.1 mmol) and 3-methylpyrazole (32 uL, 0.4 mmol) inN-methylpyrrolidinone (0.5 mL) was heated at 160° C. for 6 h. MeOH (3mL) was added and the solution was filtered through Celite. Solvent wasremoved in vacuum and residue was dissolved in DMF and purified usingreverse phase prep HPLC to afford1-(4-fluoro-7-(3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(6.9 mg) as a white solid; ¹HNMR (500 MHz, CDCl₃) δ 8.46 (d, J=2 Hz,1H), 8.19 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 7.55-7.50 (m, 5H), 6.25 (d,J=2.0 Hz, 1H), 3.78 (m, 2H), 3.56 (m, 2H), 3.35 (m, 2H), 3.25 (m, 2H),2.36 (s, 3H). LCMS: m/e 501 (M+H)⁺, ret time 2.34 min (method 2) and1-(4-fluoro-7-(5-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(13.7 mg); ¹HNMR (500 MHz, CDCl₃) δ 8.25 (m, 1H), 8.08 (bs, 1H), 7.65(m, 1H), 7.60 (m, 5H), 6.27 (m, 1H), 3.87 (m, 2H), 3.66 (m, 2H), 3.46(m, 2H), 3.36 (m, 2H), 2.83 (s, 3H). LCMS: m/e 501 (M+H)⁺, ret time 2.34min (method 2).

Preparation of1-(7-(3-amino-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-4) and1-(7-(5-amino-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-5).

A mixture of1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(100 mg, 0.2 mmol), potassium carbonate (26 mg, 0.2 mmol), copper (13mg, 0.2 mmol) and 3-aminopyrazole (100 uL, 1 mmol) inN-methylpyrrolidinone (0.5 mL) was heated at 160° C. for 5 h. Solventwas removed in vacuum and residue was dissolved in DMF and purifiedusing reverse phase prep HPLC to afford1-(7-(3-amino-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(15.9 mg) as a pale yellow solid; ¹HNMR (500 MHz, DMSO) δ 8.34 (d, J=2.0Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.03 (s, 1H), 7.70-7.58 (m, 5H), 5.92(d, J=2.5 Hz, 1H), 5.25 (m, 2H), 3.71 (m, 2H), 3.47 (m, 2H), 3.32 (m,2H), 3.16 (m, 2H). LCMS: m/e 502 (M+H)⁺, ret time 1.26 min (method 3);and1-(7-(5-amino-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(8.8 mg) as a pale yellow solid; ¹HNMR (500 MHz, CDCl₃) δ 8.21 (m, 1H),8.11 (bs, 1H), 7.60 (m, 6H), 6.94 (m, 2H), 5.52 (m, 1H), 3.71 (m, 2H),3.47 (m, 2H), 3.31 (m, 2H), 3.16 (m, 2H); LCMS: m/e 502 (M+H)⁺, ret time1.26 min (method 3).

Preparation of1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

A mixture of2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (500mg, 1.0 mmo) (compound B-1), 3-(tributylstannyl)-1H-pyrazole (358 mg, 1mmol) and tetrakis(triphenylphosphine)palladium(0) (346 mg, 0.3 mmol) in1,4-dioxane (3 mL) was heated at 110° C. for 6 h. Reaction was cooled toroom temperature, diluted with DMF and methanol, filtered through celiteand concentrated under reduced pressure. The crude was then redissolvedin DMF and purified using reverse phase HPLC to afford the titlecompound as a white solid (180 mg, 37%). ¹H NMR (500 MHz, DMSO-D₆) δ ppm3.17 (s, 2H) 3.33 (s, 2H) 3.47 (s, 2H) 3.72 (s, 2H) 6.97 (s, 1H) 7.59(s, 1H) 7.64 (s, 2H) 7.69 (s, 2H) 7.96 (s, 1H) 8.25 (s, 1H) 8.31 (s,1H). LCMS: m/e 487 (M+H)⁺, ret time 1.32 min (method 2).

Preparation of1-(4-fluoro-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(30 mg, 0.06 mmol) in DMF (1 mL) was treated with sodium hydride (60% inoil, 31.2 mg, 0.78 mmol) and stirred at room temperature for 5 min.Methyl iodide (56 uL, 0.9 mmol)was added and the mixture was stirred atrt for 1 h. Reaction was quenched with H₂O and concentrated underreduced pressure. The residue was dissolved in DMF and purified usingreverse phase prep HPLC to afford the title compound as a white solid(20 mg, 67%). ¹H NMR (500 MHz, DMSO-D₆) δ ppm 3.15 (s, 2H) 3.32 (s, 2H)3.47 (s, 2H) 3.71 (s, 2H) 4.05 (s, 3H) 6.92 (s, 1H) 7.58-7.65 (m, 3H)7.69 (s, 2H) 7.91 (s, 1H) 8.30 (d, J=12.83 Hz, 2H) 12.30 (s, 1H). LCMS:m/e 501 (M+H)⁺, ret time 1.37 min (method 3).

Preparation1-(7-(1-(2-(dimethylamino)ethyl)-H-pyrazol-3-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(40 mg, 0.08 mmol) in DMF (1 mL) was treated with sodium hydride (60% inoil, 33.0 mg, 0.8 mmol) and stirred at room temperature for 5 min.2-chloro-N,N-dimethylethanamine hydrochloride (115.2 mg, 0.8 mmol) wasadded and the mixture was stirred at rt for 1 h. Reaction was quenchedwith H₂O and concentrated under reduced pressure. The residue wasdissolved in DMF and purified using reverse phase prep HPLC to affordthe title compound as a white solid (15 mg, 34%). ¹H NMR (500 MHz, MeOD)δ ppm 2.96 (s, 6H) 3.37 (s, 2H) 3.63 (s, 2H) 3.82 (s, 2H) 3.89 (s, 2H)4.76 (s, 2H) 7.11 (s, 1H) 7.59 (s, 1H) 7.64 (s, 2H) 7.68 (s, 2H) 7.92(s, 1H) 8.25 (s, 1H) 8.36 (s, 1H). LCMS: m/e 558 (M+H)⁺, ret time 1.37min (method 3).

Preparation1-(4-fluoro-7-(1-(2-morpholinoethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(40 mg, 0.08 mmol) in DMF (1 mL) was treated with sodium hydride (60% inoil, 33 mg, 0.8 mmol) and stirred at room temperature for 5 min.4-(2-chloroethyl)morpholine (149 mg, 0.8 mmol) was added and the mixturewas stirred at rt for 1 h. Reaction was quenched with H₂O andconcentrated under reduced pressure. The residue was dissolved in DMFand purified using reverse phase prep HPLC to afford the title compoundas a white solid (20 mg, 67%). ¹H NMR (500 MHz, MeOD) δ ppm 3.43 (s, 1H)3.77 (s, 5H) 3.81 (s, 5H) 4.08 (s, 2H) 4.28 (s, 3H) 4.37 (s, 4H) 5.27(s, 6H) 7.56 (s, 1H) 8.06-8.12 (m, 2H) 8.13 (s, 2H) 8.38 (s, 1H) 8.70(s, 1H) 8.85 (s, 1H). LCMS: m/e 600 (M+H)⁺, ret time 1.22 min (method3).

Preparation4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-b]pyridine7-oxide

3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine7-oxide (2.0 g, 4.9 mmol) in a 10% aqueous solution of HCl (20 mL) washeated at 100° C. for 18 h. Reaction was concentrated under reducedpressure and the residue was washed with ethyl acetate and chloroform.NaOH (1N) was added until reaching pH=7; Then ethyl acetate was added towash the solid. Solid containing3-(carboxycarbonyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine 7-oxide wastaken to next step without further purification.

A mixture of the solid containing3-(carboxycarbonyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine 7-oxide fromabove (200 mg, 0.84 mmol), triethylamine (0.5 mL, sssss),1-(1-phenyl-1H-tetrazol-5-yl)piperazine (234 mg, 1.01 mmol) and TBTU(404 mg, 1.26 mmol) was stirred at rt in DMF (1 mL) for 24 h. H2O wasadded and the reaction mixture was concentrated under reduced pressure.The residue was purified using reverse phase prep HPLC to afford thetitle compound as a white solid (15 mg, 4%). ¹H NMR (500 MHz, CDCl₃) δppm 3.32 (s, 2H) 3.37 (s, 2H) 3.56 (s, 2H) 3.79 (s, 2H) 4.13 (s, 3H)6.83 (d, J=7.32 Hz, 1H) 7.53 (d, J=6.71 Hz, 1H) 7.54-7.60 (m, 3H) 8.16(s, 1H) 8.34 (d, J=6.71 Hz, 1H). LCMS: m/e 449 (M+H)⁺, ret time 0.99 min(method 2).

Preparation of1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-6)

To a solution of2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid(5.3 g, 20.8 mmol) (prepared as described on US20050090522A1) in DMF(100 mL) was added 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.8 g, 20.8mmol), TBTU (7.4 g, 23.0 mmol), and N,N-diisopropylethylamine (12.0 mL,68.9 mmol). The mixture was stirred at rt for 16 hr. The solvent wasremoved under reduced pressure, and the remaining residue was dissolvedin hot MeOH. Upon cooling, precipitate formed. The precipitate wascollected by filtration, and was washed with H₂O (3×75 mL). The motherliquor was concentrated under reduced pressure, then subjected to asecond crystallization using the same method. The combined precipitatesgave1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneas a light brown solid (7.3 g, 15.6 mmol). ¹H NMR (500 MHz, CDCl₃) δ9.64 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.62-7.50 (m, 5H), 4.00 (s,3H), 3.83-3.81 (m, 2H), 3.57-3.56 (m, 2H), 3.43-3.41 (m, 2H), 3.33-3.32(m, 2H). LCMS: m/e 467.3 (M+H)⁺, ret time 1.99 min (method 2).

Preparation of ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(Compound B-7)

To a suspension of1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(2.50 g, 5.35 mmol) in 1,4-dioxane (60 mL) in a sealable flask was addedethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (2.30 g, 5.36 mmol)followed by tetrakis(triphenylphosphine)palladium(0) (1.86 g, 1.61mmol). The mixture was flushed with N₂, the flask was sealed, and themixture was heated to 120° C. for 16 hr. The mixture was cooled to rtand diluted with MeOH (50 mL). The remaining solids were removed byfiltering the mixture through a pad of celite and were washed with MeOH(25 mL). The remaining solvent was concentrated under reduced pressure.The resulting residue was dissolved in MeOH, and loaded onto a silicagel. After the silica was dry, a column was run using the biotage systemwith a 0 to 10% MeOH in CH₂Cl₂ gradient. After concentrating the desiredfractions, 1.05 g of ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylatewas recovered as an orange solid. LCMS: m/e 571.2 (M+H)⁺, ret time 2.01min (method 2). 1H NMR (500 MHz, DMSO-D₆) δ ppm 12.39-12.72 (m, 1H) 8.37(s, 1H) 8.11 (s, 1H) 7.52-7.76 (m, 6H) 4.68-4.85 (m, 1H) 4.38 (q, J=7.02Hz, 2H) 3.98-4.06 (m, 3H) 3.67-3.73 (m, 2H) 3.43-3.49 (m, 2H) 3.28-3.36(m, 2H) 3.14-3.22 (m, 2H) 1.36 (t, J=7.17 Hz, 3H).

Preparation ofN-(2-hydroxyethyl)-3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFA(Compound B-8)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.100 g, 0.175 mmol) was combine with ethanolamine (0.75 mL) in asealable tube. The mixture was flushed with N₂, and the tube was sealed.The mixture was stirred for 67 hrs at rt. The mixture was diluted withDMF, and loaded onto the reverse phase prep HPLC for purification. Afterconcentrating the fractions containing product, 0.085 g of theN-(2-hydroxyethyl)-3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFAwere recovered as an off-white solid. LCMS: m/e 586.3 (M+H)⁺, ret time1.19 min (method 1). 1H NMR (300 MHz, DMSO-D₆) δ ppm 12.51 (s, 1H) 8.64(s, 1H) 8.36 (s, 1H) 8.10 (s, 1H) 7.56-7.71 (m, 6H) 7.25 (brs, 1H) 4.01(s, 3H) 3.70 (s, 2H) 3.55 (t, J=6.22 Hz, 2H) 3.27-3.48 (m, 7H) 3.16 (s,2H).

Preparation ofN-(2-(2-hydroxyethoxy)ethyl)-3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFA(Compound B-9)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.100 g, 0.175 mmol) was combine with 2-(2-aminoethoxy)ethanol (0.75mL) in a sealable tube. The mixture was flushed with N₂, and the tubewas sealed. The mixture was stirred for 67 hrs at rt. The mixture wasdiluted with DMF, and loaded onto a reverse phase prep HPLC forpurification. After concentrating the fractions containing product,0.064 g of theN-(2-(2-hydroxyethoxy)ethyl)-3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFAwere recovered as an off-white solid. LCMS: m/e 630.2 (M+H)⁺, ret time1.84 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.55-8.62 (m, 1H)7.99-8.07 (m, 1H) 7.53-7.75 (m, 6H) 4.07-4.18 (m, 3H) 3.79-3.88 (m, 2H)3.58-3.76 (m, 8H) 3.29-3.43 (m, 6H).

Preparation of3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazole-5-carboxamide.TFA(Compound B-10)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.100 g, 0.175 mmol) was combine with 1-(3-aminopropyl)-4-methylpiperazine (0.75 mL) in a sealable tube. The mixture was flushed withN₂, and the tube was sealed. The mixture was stirred for 67 hrs at rt.The mixture was diluted with DMF, and loaded onto a reverse phase prepHPLC for purification. After concentrating the fractions containingproduct, 0.093 g of the3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazole-5-carboxamide.TFAwere recovered as an off-white solid. LCMS: m/e 682.4 (M+H)⁺, ret time1.11 min (method 1). 1H NMR (300 MHz, DMSO-D6) δ ppm 12.48 (s, 1H) 10.82(s, 1H) 8.82 (s, 1H) 8.35 (s, 1H) 8.11 (s, 1H) 7.53-7.72 (m, 6H) 4.01(s, 3H) 3.10-3.79 (m, 20H) 2.89 (s, 3H) 1.88-2.03 (m, 2H).

Preparation of3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.TFA(Compound B-11)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.100 g, 0.175 mmol) was combine with 1-(2-aminoethyl)-pyrrolidine(0.75 mL) in a sealable tube. The mixture was flushed with N₂, and thetube was sealed. The mixture was stirred for 67 hrs at rt. The mixturewas diluted with DMF, and loaded onto a reverse phase prep HPLC forpurification. After concentrating the fractions containing product,0.100 g of the3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.TFAwere recovered as dark orange solid. LCMS: m/e 639.3 (M+H)⁺, ret time1.78 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.56 (s, 1H) 8.06 (s,1H) 7.55-7.73 (m, 6H) 4.11 (s, 3H) 3.79-3.92 (m, 4H) 3.13-3.67 (m, 12H)2.03-2.25 (m, 4H).

Preparation of3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxamide.TFA(Compound B-12)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.100 g, 0.175 mmol) was combine with 4-(2-aminoethyl)-pyridine (0.75mL) in a sealable tube. The mixture was flushed with N₂, and the tubewas sealed. The mixture was stirred for 67 hrs at rt. The mixture wasdiluted with DMF, and loaded onto a reverse phase prep HPLC forpurification. After concentrating the fractions containing product,0.035 g of the3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxamide.TFAwere recovered as an off-white solid. LCMS: m/e 647.2 (M+H)⁺, ret time1.77 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.74-8.83 (m, 2H)8.52-8.60 (m, 1H) 8.02-8.12 (m, 3H) 7.56-7.74 (m, 6H) 4.08-4.16 (m, 3H)3.79-3.90 (m, 4H) 3.59-3.67 (m, 2H) 3.28-3.45 (m, 6H).

Preparation of3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-morpholinoethyl)-1H-pyrazole-5-carboxamide.TFA(Compound B-13)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.075 g, 0.131 mmol) was combine with 4-(2-aminoethyl)morpholine (0.75mL) in a sealable tube. The mixture was flushed with N₂, and the tubewas sealed. The mixture was stirred for 67 hrs at rt. The mixture wasdiluted with DMF, and loaded onto a reverse phase prep HPLC forpurification. After concentrating the fractions containing product,0.073 g of the3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-morpholinoethyl)-1H-pyrazole-5-carboxamide.TFAwere recovered as an off-white solid. LCMS: m/e 655.3 (M+H)⁺, ret time1.74 min (method 2). 1H NMR (300 MHz, MeOD) δ ppm 8.57 (s, 1H) 8.07 (s,1H) 7.56-7.74 (m, 6H) 3.17-4.17 (m, 23H).

Preparation of3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.TFA(Compound B-14)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.100 g, 0.175 mmol) was combine with 1-(2-aminomethyl)piperazine (0.75mL) in a sealable tube. The mixture was flushed with N₂, and the tubewas sealed. The mixture was stirred for 67 hrs at rt. The mixture wasdiluted with DMF, and loaded onto a reverse phase prep HPLC forpurification. After concentrating the fractions containing product,0.089 g of the3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.TFAwere recovered as a tan solid. LCMS: m/e 654.3 (M+H)⁺, ret time 1.73 min(method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.54-8.62 (m, 1H) 8.01-8.10 (m,1H) 7.54-7.74 (m, 6H) 4.08-4.16 (m, 3H) 3.77-3.89 (m, 4H) 3.60 (s, 10H)3.22-3.47 (m, 6H).

Preparation ofN-(3-(dimethylamino)propyl)-3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFA(Compound B-15)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.125 g, 0.219 mmol) was combine with 3-dimethylaminopropylamine (0.70mL) in a sealable tube. The mixture was flushed with N₂, and the tubewas sealed. The mixture was stirred for 36 hrs at rt. The mixture wasdiluted with DMF, and loaded onto a reverse phase prep HPLC forpurification. After concentrating the fractions containing product,0.010 g of theN-(3-(dimethylamino)propyl)-3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFAwere recovered as an off-white solid. LCMS: m/e 627.6 (M+H)⁺, ret time1.75 min (method 2). 1H NMR (300 MHz, DMSO-D₆) δ ppm 8.78-9.19 (m, 2H)8.23 (s, 1H) 8.09 (s, 1H) 7.55-7.73 (m, 6H) 4.00 (s, 3H) 2.70-2.79 (m,6H) 2.68-3.93 (m, 12H) 1.96-2.15 (m, 2H).

Preparation ofN-(2-(dimethylamino)ethyl)-3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFA(Compound B-16)

Ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.05 g, 0.088 mmol) was combine with N,N-dimethylethylenediamine (0.70mL) in a sealable tube. The mixture was flushed with N₂, and the tubewas sealed. The mixture was stirred for 38 hrs at rt. The mixture wasdiluted with DMF, and loaded onto a reverse phase prep HPLC forpurification. After concentrating the fractions containing product,0.020 g of theN-(2-(dimethylamino)ethyl)-3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFAwere recovered as a tan solid. LCMS: m/e 613.2 (M+H)⁺, ret time 1.75 min(method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.56 (s, 1H) 8.08 (s, 1H)7.59-7.73 (m, 6H) 4.13 (s, 3H) 3.82-3.86 (m, 4H) 3.62-3.66 (m, 2H)3.40-3.48 (m, 4H) 3.33-3.37 (m, 2H) 3.03 (s, 6H).

Preparation of1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-17)

4-fluoro-1H-pyrrolo[2,3-c]pyridin-7-amine (2.26 g, 15 mmol) was added toa mixture of AlCl₃ (12.0 g, 90.0 mmol) and ethylmethylimidazoliumchloride (4.38 g, 30.0 mmol). Methyl chlorooxoacetate (3.6 mL, 30.0mmol) was added slowly to the above solution and the mixture was stirredat rt for 3 h. Reaction flask was placed in an ice bath and water wasslowly added until a white precipitate formed. The solid was collectedby filtration and suspended in DMF. TEA (7 mL) was added and the mixturewas stirred at rt for 1 h. Solvent was removed in vacuum. Chloroform (50mL) was added and the solid was collected by filtration to afford2-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid as abright yellow solid (2.3 g, 90% pure). LCMS: m/e 238 (M+H)⁺, ret time0.96 min (method 3).

2-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.3g, 10.0 mmol) was dissolved in DMF (66 mL) and treated with1-(1-phenyl-1H-tetrazol-5-yl)piperazine (2.31 g, 10.0 mmol),triethylamine (2.8 mL, 20.0 mmol) and TBTU (3.5 g, 11.0 mmol) and acatalytic amount of DMAP. The reaction mixture was stirred at rt for 18h. Solvent was removed in vacuum and water was added. A white solidprecipitated out and it was collected by filtration and recrystallizedwith MeOH to afford the title compound (2.4 g) as a yellow solid. ¹HNMR(500 MHz, DMSO-D₆) δ 8.53 (s, 1H), 7.81 (d, J=4.0 Hz; 1H), 7.75-7.54 (m,5H), 3.69 (m, 2H), 3.44 (m, 2H), 3.33 (m, 2H), 3.17 (m, 2H). LCMS: m/e436 (M+H)⁺, ret time 1.73 min (method 2).

Preparation ofN-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)acetamide(Compound B-18)

1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(100 mg, 0.23 mmol) was dissolved in pyridine (2 mL) and the mixture washeated at 50° C. Acetyl chloride (65 uL, 0.92 mmol) was added and themixture was stirred at this temperature for 1 h. Solvent was removed invacuum and the residue was purified using reverse phase prep HPLC toafford the title compound as a white solid (55 mg). ¹HNMR (500 MHz,DMSO-D₆) δ 8.34 (s, 1H), 8.04 (d, J=1.0 Hz, 1H), 7.70-7.58 (m, 5H), 3.69(m, 2H), 3.45 (m, 2H), 3.34 (m, 2H), 3.16 (m, 2H), 2.17 (s, 3H). LCMS:m/e 478 (M+H)⁺, ret time 1.07 min (method 3).

Preparation of3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,1-dimethylurea(Compound B-19)

1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(100 mg, 0.23 mmol) was dissolved in pyridine (1 mL). Dimethylcarbamylchloride (0.21 mL, 2.3 mmol) was added and the mixture was heated at 50°C. for 18 h. Solvent was removed in vacuum and the residue was purifiedusing reverse phase prep HPLC to afford the title compound as a pale tansolid (10 mg). ¹HNMR (500 MHz, DMSO-D₆) δ 8.89 (s, 1H), 8.25 (s, 1H),7.70-7.59 (m, 5H), 3.67 (m, 2H), 3.44 (m, 2H), 3.37 (m, 2H), 3.20 (m,2H), 3.11 (s, 3H), 2.88 (s, 3H). LCMS: m/e 507 (M+H)⁺, ret time 1.04 min(method 3).

Preparation ofN¹-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N²,N²-dimethyloxalamide(Compound B-20)

1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(100 mg, 0.23 mmol) was dissolved in DMF (2 mL) and treated withN,N-dimethyloxamic acid (27 mg, 0.23 mmol), Hunig's base (0.14 mL, 0.8mmol) and TBTU (81 mg, 0.25 mmol). The reaction mixture was stirred atrt for 18 h. Solvent was removed in vacuum and water was added. A solidprecipitated out and it was collected by filtration, dissolved in DMFand purified using reverse phase prep HPLC to afford the title compoundas a pale yellow solid (11 mg). ¹HNMR (500 MHz, DMSO-D₆) δ 8.47 (s, 1H),8.16 (s, 1H), 7.70-7.50 (m, 5H), 5.76 (m, 1H), 4.10-3.10 (m, 6H), 3.16(s, 6H). LCMS: m/e 535 (M+H)⁺, ret time 1.33 min (method 1).

Preparation of 3-(tributylstannyl)-1H-pyrazole-5-carbaldehyde and(3-(tributylstannyl)-1H-pyrazol-5-yl)methanol

A solution of ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (3.94g, 9.18 mmol) in toluene (10 mL) was cooled −78° C. A 1M solution ofDIBAL-H in toluene (11.5 mL, 11.5 mmol) was slowly added to the mixture.The mixture was warmed to 0° C. and stirred for 9 h. After the 9 h, themixture was carefully quenched with H₂O (50 mL) while the mixture wasstill being cooled. The mixture was partitioned with EtOAc, and thecompound was extracted (4×75 mL) with EtOAc. The combined organic layerswere washed with saturated NaCl, dried with Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was then loaded onto asilica gel column, and purified using the biotage system with a 0 to 40%EtOAc in hexanes gradient to first remove the aldehyde and unreactedstarting material. The column was then flushed with a 50% CH₂Cl₂ in MeOHsolution to remove the remaining alcohol. After concentrating thedesired fractions, 3-(tributylstannyl)-1H-pyrazole-5-carbaldehyde (1.125g) was recovered as a clear, colorless oil, and(3-(tributylstannyl)-1H-pyrazol-5-yl)methanol (0.525 g) was recovered asa white solid. LCMS: m/e 387.2 (M+H)⁺, ret time 2.01 min (method 3) for3-(tributylstannyl)-1H-pyrazole-5-carbaldehyde and LCMS: m/e 389.3(M+H)⁺, ret time 2.59 min (method 2) for(3-(tributylstannyl)-1H-pyrazol-5-yl)methanol.

The following amino pyrazole intermediates were formed by thestandardized reductive amination procedure that follows:

-   2-((3-(tributylstannyl)-1H-pyrazol-5-yl)methylamino)ethanol    (pyrazole 1)-   N¹,N¹-dimethyl-N²-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethane-1,2-diamine    (pyrazole 2)-   N¹,N¹,N²-trimethyl-N²-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethane-1,2-diamine(pyrazole    3)-   2-(pyridin-4-yl)-N-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethanamine    (pyrazole 4)

To a solution of 3-(tributylstannyl)-1H-pyrazole-5-carbaldehyde (1.0 eq,approximately 0.5 mmol scale) in DCE (2-3 mL) was added AcOH (1.0 eq)followed by the amine (1.05-1.1 eq), and finally Sodiumtriacetoxyborohydride (1.4 eq). The mixture was stirred at roomtemperature for 1-3 h. The mixture was made basic with 1N NaOH (pH=13)and was extracted three times with CH₂Cl₂. The combined organic layerswere dried with Na₂SO₄, the drying agent was removed by filtration, andresulting solution was concentrated under reduced pressure. No furtherpurification was necessary. LCMS: m/e 432.1 (M+H)⁺, ret time 2.52 min(method 2) for2-((3-(tributylstannyl)-1H-pyrazol-5-yl)methylamino)ethanol. LCMS: m/e459.2 (M+H)⁺, ret time 3.44 min (method 4) forN1,N1-dimethyl-N2-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethane-1,2-diamine.LCMS: m/e 473.3.1 (M+H)⁺, ret time 2.65 min (method 2) forN¹,N¹,N²-trimethyl-N²-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethane-1,2-diamine.LCMS: m/e 493.6 (M+H)⁺, ret time 4.29 min (method 5) for2-(pyridin-4-yl)-N-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethanamine.

Preparation of3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid (Compound B-21)

To a suspension of ethyl3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.124 g, 0.217 mmol) in DMF (1.5 mL) and H₂O (1.5 mL) was added LiOHmonohydrate (0.027 g, 0.651 mmol). The mixture was heated to 120° C. for24 h. The reaction was not complete, so an additional 0.05 g of LiOHhydrate along with 2 mL of H₂O were added to the mixture, and it wasagain heated to 120° C. After 24 h of heating, the reaction was nearlycomplete by LCMS, so it was cooled to rt, and made acidic (pH=1) with 6NHCl. The mixture was diluted with H₂O, and partitioned with EtOAc. Theproduct precipitated from between the two layers, and was collected byfiltration. The solids were washed with cold MeOH and H₂O. The3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid (0.08 g) was collected as a light yellow solid. LCMS: m/e 542.97(M+H)⁺, ret time 1.86 min (method 2). 1H NMR (500 MHz, DMSO-D₆) δ ppm12.10-12.22 (s, 1H) 8.25 (s, 1H) 8.10 (s, 1H) 7.56-7.77 (m, 5H) 7.39 (s,1H) 3.99 (s, 3H) 3.67-3.72 (m, 2H) 3.40-3.46 (m, 2H) 3.29-3.36 (m, 2H)3.14-3.20 (m, 2H).

Preparation of1-(7-(5-(hydroxymethyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-22)

In a sealable, flask a mixture of1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.150 g, 0.321 mmol) in 1,4-dioxane (5 mL) was prepared.(3-(tributylstannyl)-1H-pyrazol-5-yl)methanol (0.137 g, 0.353 mmol) wasadded followed by tetrakis(triphenylphosphine)palladium (0) (0.150 g,0.130 mmol). The mixture was flushed with N₂, and flask was sealed. Themixture was then heated to 120° C. for 14 h. After cooling to rt, themixture was diluted with DMF, and filtered through a plug of celite toremove any solids. The liquid was concentrated under reduced pressure,and the residue was dissolved in DMF. The DMF solution was purified byprep HPLC to give 0.037 g of an off-white solid as the1-(7-(5-(hydroxymethyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione.LCMS: m/e 529.2 (M+H)⁺, ret time 1.78 min (method 2). 1H NMR (500 MHz,MeOD) δ ppm 8.65 (s, 1H) 7.98 (s, 1H) 7.56-7.80 (m, 5H) 7.16 (s, 1H)4.81 (s, 2H) 4.15 (s, 3H) 3.83-3.87 (m, 2H) 3.63-3.68 (m, 2H) 3.40-3.44(m, 2H) 3.34-3.39 (m, 2H).

Preparation of N¹,N¹-dimethyl-N²-(1H-pyrazol-3-yl)ethane-1,2-diamine

3-aminopyrazole (5.0 g, 60.2 mmol) was dissolved in AcOH (20 mL). A 50%in H₂O solution of chloroacetaldehyde (8.0 mL, 63.2 mmol) was slowlyadded to the mixture. The mixture was cooled to 0° C., and sodiumcyanoborohydride (4.2 g, 66.8 mmol) was added in two portions over tenminutes to the cooled solution. The mixture was warmed to rt and stirredfor 5 h. The mixture was carefully made basic with 1N NaOH to pH=10. Themixture was partitioned with CH₂Cl₂, and was extracted five times. Thecombined organic layers were dried with MgSO₄, filtered, andconcentrated under reduced pressure. A column was run to purify theproduct using a 0 to 5% MeOH in CH₂Cl₂ gradient. The resultingN-(2-chloroethyl)-1H-pyrazol-3-amine was recovered as a clear, colorlessoil (2.1 g). LCMS: m/e 146.2 (M+H)⁺, ret time 0.72 min (method 3).

In a sealable flask, the N-(2-chloroethyl)-1H-pyrazol-3-amine (0.214 g,1.47 mmol) were combined with 1.5 mL of dimethylamine (40% in H₂O). Themixture flask was sealed, and the mixture was heated to 100° C. fir 16h. The mixture was cooled to rt, and transferred to a rb flask withMeOH. The solvent was removed under reduced pressure to give theN1,N1-dimethyl-N2-(1H-pyrazol-3-yl)ethane-1,2-diamine in quantitativeyield. LCMS: m/e 155.3 (M+H)⁺, ret time 0.96 min (method 3).

Preparation of1-(7-(3-(2-(dimethylamino)ethylamino)-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneTFA (Compound B-23)

1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.100 g, 0.200 mmol) was combined with theN¹,N¹-dimethyl-N²-(1H-pyrazol-3-yl)ethane-1,2-diamine (0.140 g, 0.200mmol), 1-methyl-2-pyrrolidinone (0.5 mL), K₂CO₃ (0.028 g, 0.200 mmol),and Cu powder (0.013 g, 0.200 mmol). The mixture was heated to 160° C.for 4.5 h. The mixture was cooled to rt, and diluted with DMF. The DMFmixture was filtered through a pad of celite to remove any solids, andthe solution was purified by prep HPLC. After purification, the1-(7-(3-(2-(dimethylamino)ethylamino)-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione.TFA(0.010 g) was recovered as a brown solid. LCMS: m/e 573.5 (M+H)⁺, rettime 1.88 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.42 (d, J=2.52Hz, 1H) 8.30 (s, 1H) 7.95 (d, J=2.06 Hz, 1H) 7.56-7.72 (m, 5H) 6.01 (d,J=2.75 Hz, 1H) 3.78-3.86 (m, 4H) 3.59-3.64 (m, 2H) 3.42-3.46 (m, 2H)3.34-3.39 (m, 4H) 2.95 (s, 6H)

Preparation of1-(7-(5-((2-hydroxyethylamino)methyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneTFA (Compound B-24)

In a sealable flask, a mixture of1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.240 g, 0.509 mmol) in 1,4-dioxane (5 mL) was prepared.2-((3-(tributylstannyl)-1H-pyrazol-5-yl)methylamino)ethanol (0.241 g,0.560 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (0.177 g, 0.153 mmol). The mixture was flushed with N₂, and flaskwas sealed. The mixture was then heated to 120° C. for 14 h. Aftercooling to rt, the mixture was diluted with DMF, and filtered through aplug of celite to remove any solids. The liquid was concentrated underreduced pressure, and the residue was dissolved in DMF. The DMF solutionwas purified by prep HPLC to give 0.050 g of a light yellow solid as the1-(7-(5-((2-hydroxyethylamino)methyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione.TFA.LCMS: m/e 572.5 (M+H)⁺, ret time 1.68 min (method 2). 1H NMR (500 MHz,MeOD) δ ppm 8.57 (s, 1H) 8.06 (s, 1H) 7.60-7.75 (m, 5H) 7.42 (s, 1H)4.54 (s, 2H) 4.14 (s, 3H) 3.83-3.91 (m, 4H) 3.62-3.68 (m, 2H) 3.24-3.45(m, 6H).

Preparation of1-(7-(5-((2-(dimethylamino)ethylamino)methyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneTFA (Compound B-25)

In a sealable flask, a mixture of1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.140 g, 0.306 mmol) in 1,4-dioxane (5 mL) was prepared.2-((3-(tributylstannyl)-1H-pyrazol-5-yl)methylamino)ethanol (0.14 g,0.306 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (0.106 g, 0.092 mmol). The mixture was flushed with N₂, and flaskwas sealed. The mixture was then heated to 120° C. for 15 h. Aftercooling to rt, the mixture was diluted with DMF, and filtered through aplug of celite to remove any solids. The liquid was concentrated underreduced pressure, and the residue was adsorbed to silica gel. A flashcolumn was run using a 0 to 100% MeOH in CH₂Cl₂ gradient. Still theproduct was on the column, so it was flushed with DMF to remove theproduct. The DMF was mostly removed under reduced pressure, and wasfurther removed by dissolving the product in CH₂Cl₂ and washing theorganic layer 5 times with H₂O. The organic layer was dried with Na₂SO₄,was filtered, and concentrated under reduced pressure. The1-(7-(5-((2-(dimethylamino)ethylamino)methyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione.TFA(0.053 g) was recovered as a light yellow solid. LCMS: m/e 599.4 (M+H)⁺,ret time 1.73 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.27 (s, 1H)7.95 (s, 1H) 7.54-7.68 (m, 5H) 6.92 (s, 1H) 4.02 (s, 3H) 3.93 (s, 2H)3.77-3.82 (m, 2H) 3.52-3.58 (m, 2H) 3.35-3.40 (m, 2H) 3.24-3.30 (m, 2H)2.78 (t, J=6.71 Hz, 2H) 2.53 (t, J=6.71 Hz, 2H) 2.28 (s, 6H).

Preparation of1-(7-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneTFA (Compound B-26)

In a sealable flask, a mixture of1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.165 g, 0.353 mmol) in 1,4-dioxane (5 mL) was prepared.N¹,N¹,N²-trimethyl-N²-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethane-1,2-diamine(0.175 g, 0.371 mmol) was added followed bytetrakis(triphenylphosphine)palladium (0) (0.122 g, 0.106 mmol). Themixture was flushed with N₂, and flask was sealed. The mixture was thenheated to 120° C. for 15 h. After the reaction was incomplete by LCMS,an additional 0.050 g ofN¹,N¹,N²-trimethyl-N²-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethane-1,2-diaminewas added along with 0.075 g of tetrakis(triphenylphosphine)palladium(0). The mixture was flushed with N₂, sealed, and reheated to 120° C.for 6 h. After cooling to rt, the mixture was diluted with DMF, andfiltered through a plug of celite to remove any solids. The liquid wasconcentrated under reduced pressure, and the residue was dissolved inDMF. The DMF solution was purified by prep HPLC to give 0.040 g of alight yellow solid as the1-(7-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione.TFA.LCMS: m/e 613.4 (M+H)⁺, ret time 1.80 min (method 2). 1H NMR (500 MHz,MeOD) δ ppm 8.66 (s, 1H) 8.06 (s, 1H) 7.59-7.74 (m, 5H) 7.45 (s, 1H)4.33 (s, 2H) 4.15 (s, 3H) 3.82-3.87 (m, 2H) 3.62-3.67 (m, 2H) 3.56 (t,J=6.56 Hz, 2H) 3.39-3.44 (m, 2H) 3.32-3.38 (m, 4H) 2.99 (s, 6H)2.66-2.69 (m, 3H).

Preparation of1-(4-methoxy-7-(5-((2-(pyridin-4-yl)ethylamino)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneTFA (Compound B-27)

In a sealable flask, a mixture of1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.195 g, 0.417 mmol) in 1,4-dioxane (7 mL) was prepared.2-(pyridin-4-yl)-N-((3-(tributylstannyl)-1H-pyrazol-5-yl)methyl)ethanamine(0.205 g, 0.417 mmol) was added followed bytetrakis(triphenylphosphine)palladium (0) (0.144 g, 0.125 mmol). Themixture was flushed with N₂, and flask was sealed. The mixture was thenheated to 120° C. for 14 h. After cooling to rt, the mixture was dilutedwith CH₂Cl₂ and MeOH, and filtered through a plug of celite to removeany solids. Solids were washed with MeOH to be sure no product was leftbehind. The liquid was concentrated under reduced pressure, and theresidue was dissolved in DMF. The DMF solution was purified by prep HPLCto give 0.028 g of a light yellow solid as the1-(7-(5-((2-hydroxyethylamino)methyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione.TFA.LCMS: m/e 633.4 (M+H)⁺, ret time 1.70 min (method 2). 1H NMR (500 MHz,MeOD) δ ppm 8.80-8.85 (m, J=6.10 Hz, 2H) 8.60 (s, 1H) 8.05-8.10 (m, 3H)7.59-7.73 (m, 5H) 7.50 (s, 1H) 4.61 (s, 2H) 4.14 (s, 3H) 3.81-3.87 (m,2H) 3.60-3.68 (m, 4H) 3.04-3.07 (m, 6H).

Preparation of ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate

To a sealed tube containing1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound B-1) (1.24 g, 2.48 mmol) in 1,4-dioxane (20 mL) was addedethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (1.12 g, 2.61 mmol)and Pd(PPh₃)₄ (0.87 g, 0.75 mmol). The mixture was flushed with N₂, andwas sealed and heated to 100° C. After 14 h of heating, the mixture wascooled to rt, was diluted with MeOH, and was filtered through a pad ofcelite to remove any solids. The solution was concentrated under reducedpressure, and was re-dissolved in DMF. The DMF solution was loaded onthe prep HPLC for purification. After purification, the title productwas isolated as an off-white solid (0.901 g). LCMS: m/e 559.6 (M+H)⁺,ret time 2.283 min (method 2). 1H NMR (500 MHz, DMSO-D₆) δ ppm 14.52 (s,1H) 12.35 (s, 1H) 8.26-8.41 (m, 2H) 7.36-7.76 (m, 6H) 4.29-4.47 (m,J=6.71 Hz, 2H) 3.09-3.80 (m, 8H) 1.36 (s, 3H).

Preparation of3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid

To a rb flask containing ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.058 g, 0.10 mmol) in DMF (5 mL) and water (5 mL) was added lithiumhydroxide monohydrate (0.044 g, 1.05 mmol). The mixture was heated to100° C. for 21.5 h. The mixture was cooled to rt, and HCl was added toPH=1. Solids precipitated out of solution, and were collected byfiltration to give the title compound as a yellow solid (0.03 g). LCMS:m/e 531.15 (M+H)⁺, ret time 2.10 min (method 2). 1H NMR (500 MHz,DMSO-D₆) δ ppm 14.37 (s, 1H) 13.58 (s, 1H) 12.23 (s, 1H) 8.21-8.42 (m,2H) 7.52-7.77 (m, 5H) 7.35 (s, 1H) 3.08-3.76 (m, 8H).

C-7 Pyrazole carboxamides were made using two different methods. Ageneral procedure for each method is provided along withcharacterizations of those compounds from each method.

To a flask containing of3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid (0.02-0.07 g, 1 equiv) in DMF (2 mL) was added Hunig's base (0.2mL) followed by the amine (1.2 equiv) and TBTU (1.1 equiv). The mixturewas flushed with N₂, and was stirred at rt. After 15-72 h, the mixturewas quenched with water and the solution was concentrated under reducedpressure. The resulting residue was dissolved in DMF, and filteredthrough a pad of celite to remove any remaining solids. The DMF solutionwas purified by prep HPLC to give the amide products as their TFA salts.

Mass LC/MS recovered (M + 1) Retention after (Method time R₁ R₂purification 2) (minutes) Compound Name

CH₃   7 mg 615.8 1.90 N-(2- (dimethylamino)ethyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1- phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)- 1H-pyrrolo[2,3-c]pyridin-7-yl)-N-methyl-1H-pyrazole- 5-carboxamide•TFA

CH₃   31 mg 588.3 2.01 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5- yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7- yl)-N-(2-hydroxyethyl)-N-methyl-1H-pyrazole-5- carboxamide•TFA

H 14.8 mg 574.6 2.01 3-(4-fluoro-3-(2-oxo-2-(4- (1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)- 1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-hydroxyethyl)-1H- pyrazole-5- carboxamide•TFA

CH₃  9.4 mg 629.6 1.90 N-(3- (dimethylamino)propyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1- phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)- 1H-pyrrolo[2,3-c]pyridin-7-yl)-N-methyl-1H-pyrazole- 5-carboxamide•TFA

H   13 mg 670.4 1.87 3-(4-fluoro-3-(2-oxo-2-(4- (1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)- 1H-pyrrolo[2,3-c]pyridin-7- yl)-N-(3-(4-methylpiperazin-1- yl)propyl)-1H-pyrazole-5- carboxamide•TFA

Compound:N-(2-(dimethylamino)ethyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-methyl-1H-pyrazole-5-carboxamide.TFA

1H NMR (500 MHz, MeOD) δ ppm 8.37-8.42 (m, 1H) 8.29 (s, 1H) 7.58-7.74(m, 5H) 7.49 (s, 1H) 3.97-4.04 (m, 2H) 3.82-3.87 (m, 2H) 3.61-3.67 (m,2H) 3.27-3.55 (m, 9H) 3.06 (s, 6H)

Compound:3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-hydroxyethyl)-N-methyl-1H-pyrazole-5-carboxamide.TFA

1H NMR (500 MHz, MeOD) δ ppm 8.45 (s, 1H) 8.28 (d, J=2.75 Hz, 1H)7.57-7.71 (m, 5H) 7.42 (d, J=6.71 Hz, 1H) 3.71-3.89 (m, 6H) 3.62-3.66(m, 2H) 3.16-3.46 (m, 7H)

Compound:3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-hydroxyethyl)-1H-pyrazole-5-carboxamide.TFA

1H NMR (500 MHz, MeOD) δ ppm 8.39 (s, 1H) 8.24 (d, J=2.44 Hz, 1H)7.57-7.71 (m, 5H) 7.44 (s, 1H) 3.81-3.85 (m, 2H) 3.76 (t, J=5.65 Hz, 2H)3.61-3.66 (m, 2H) 3.55 (t, J=5.65 Hz, 2H) 3.36-3.41 (m, 2H) 3.29-3.35(m, 2H)

Compound:N-(3-(dimethylamino)propyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-methyl-1H-pyrazole-5-carboxamide.TFA

1H NMR (500 MHz, MeOD) δ ppm 8.40 (s, 1H) 8.29 (s, 1H) 7.59-7.73 (m, 5H)7.47 (s, 1H) 3.81-3.87 (m, 2H) 3.69-3.76 (m, 2H) 3.62-3.66 (m, 2H)3.16-3.48 (m, 7H) 2.97 (s, 6H) 2.87-2.91 (m, 2H) 2.11-2.25 (m, 2H)

Compound:3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazole-5-carboxamide.TFA

1H NMR (500 MHz, MeOD) δ ppm 8.37 (s, 1H) 8.27 (d, J=2.44 Hz, 1H)7.58-7.74 (m, 5H) 7.46 (s, 1H) 3.80-3.86 (m, 2H) 3.60-3.66 (m, 2H)3.27-3.58 (m, 14H) 3.05-3.12 (m, 2H) 2.94 (s, 3H) 1.99-2.07 (m, 2H)

Method 2

To a sealable flask containing ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.05 g, 0.09 mmol) was added the amine (0.5 mL). The mixture wasstirred at rt for three days, then was diluted with DMF and passedthrough a pad of celite to remove any solids. The DMF solution was thenpurified by prep HPLC to give the desired amide products.

Mass LC/MS recovered (M + 1) Retention after (Method time R₁ R₂purification 2) (minutes) Compound Name

H 39.7 mg 627.4 1.92 3-(4-fluoro-3-(2-oxo-2-(4- (1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)- 1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(pyrrolidin-1- yl)ethyl)-1H-pyrazole-5- carboxamide•TFA

H 40.2 mg 635.3 1.94 3-(4-fluoro-3-(2-oxo-2-(4- (1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)- 1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(pyridin-4- yl)ethyl)-1H-pyrazole-5- carboxamide•TFA

H 23.6 mg 643.5 1.91 3-(4-fluoro-3-(2-oxo-2-(4- (1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)- 1H-pyrrolo[2,3-c]pyridin- 7-yl)-N-(2-morpholinoethyl)-1H- pyrazole-5- carboxamide•TFA

Compound:3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.TFA

1H NMR (500 MHz, MeOD) δ ppm 8.38 (s, 1H) 8.25 (d, J=2.44 Hz, 1H)7.56-7.70 (m, 5H) 7.45 (s, 1H) 3.78-3.89 (m, 6H) 3.61-3.66 (m, 2H) 3.50(t, J=5.80 Hz, 2H) 3.35-3.41 (m, 2H) 3.29-3.35 (m, 2H) 3.16-3.26 (m, 2H)2.01-2.26 (m, 4H).

Compound:3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxamide.TFA

1H NMR (500 MHz, MeOD) δ ppm 8.78 (d, J=6.71 Hz, 2H) 8.37 (s, 1H) 8.23(d, J=2.44 Hz, 1H) 8.07 (d, J=6.71 Hz, 2H) 7.62-7.69 (m, 5H) 7.38 (s,1H) 3.80-3.86 (m, 4H) 3.61-3.64 (m, 2H) 3.28-3.41 (m, 6H).

Compound:3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-morpholinoethyl)-1H-pyrazole-5-carboxamide.TFA

1H NMR (500 MHz, MeOD) δ ppm 8.38 (s, 1H) 8.27 (d, J=2.75 Hz, 1H)7.58-7.71 (m, 5H) 7.47 (s, 1H) 4.11 (s, 2H) 3.68-3.89 (m, 8H) 3.63 (d,J=4.88 Hz, 4H) 3.61-3.65 (m, 2H) 3.48 (t, J=5.95 Hz, 2H) 3.37-3.40 (m,2H).

Preparation of ethyl3-(4-fluoro-1-methyl-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylateand ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.050 g, 0.09 mmol) in DMF (2 mL) was added a 2M in THF solution ofNaHMDS (0.11 mL, 0.22 mmol) dropwise followed by MeI (0.05 mL, 0.9mmol). The mixture was stirred for 60 minutes at rt, and was quenchedwith 2 mL H₂O. The solvent was removed under reduced pressure, and theresidue was re-dissolved in DMF. The DMF solution was passed through aplug of celite to remove any remaining solids, and was purified by prepHPLC to give ethyl3-(4-fluoro-1-methyl-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate(0.011 g) and ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate(0.011 g) as the products.

Ethyl3-(4-fluoro-1-methyl-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate:LCMS: m/e 587.7 (M+H)⁺, ret time 2.213 min (method 2). 1H NMR (500 MHz,MeOD) δ ppm 8.42 (s, 1H) 8.31 (s, 1H) 7.51-7.70 (m, 5H) 7.25 (s, 1H)4.40 (q, J=6.92 Hz, 2H) 4.27 (s, 3H) 3.77-3.83 (m, 2H) 3.73 (s, 3H)3.57-3.63 (m, 2H) 3.33-3.40 (m, 2H) 3.26-3.33 (m, 2H) 1.39 (t, J=7.02Hz, 3H).

Ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate:LCMS: m/e 573.5 (M+H)⁺, ret time 1.747 min (method 1). 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 11.55 (s, 1H) 8.43 (s, 1H) 8.29 (s, 1H) 7.73 (s, 1H)7.48-7.67 (m, 5H) 4.35-4.48 (m, 2H) 4.31 (s, 3H) 3.80-3.89 (m, 2H)3.62-3.72 (m, 2H) 3.30-3.47 (m, 4H) 1.34-1.49 (m, 3H).

Preparation of3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide.TFA.

To a sealable flask containing ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate(0.047 g, 0.08 mmol) was added ethanolamine (0.7 mL). The mixture wassealed and heated to 50° C. for 20.5 h. The mixture was cooled to rt,and was diluted with DMF and was passed through a plug of celite toremove any solids. The DMF solution was purified by prep HPLC to give3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide.TFA(0.014 g) as an off-white solid. LCMS: m/e 588.7 (M+H)⁺, ret time 2.03min (method 2) 1H NMR (500 MHz, CDCl₃) δ ppm 8.35 (s, 1H) 8.23 (s, 1H)7.50-7.61 (m, 6H) 4.29 (s, 3H) 3.78-3.85 (m, 4H) 3.54-3.64 (m, 4H) 3.40(s, 2H) 3.29-3.34 (m, 2H) 2.79 (s, 1H).

Preparation ofN-(3-(dimethylamino)propyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide.TFA

To a sealable flask containing ethyl3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate(0.058 g, 0.10 mmol) was added N1,N1-dimethylpropane-1,3-diamine (0.7mL). The mixture was sealed and heated to 50° C. for 20.5 h. The mixturewas cooled to rt, and was diluted with DMF and was passed through a plugof celite to remove any solids. The DMF solution was purified by prepHPLC to giveN-(3-(dimethylamino)propyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide.TFA.(0.020 g) as an off-white solid. LCMS: m/e 629.5 (M+H)⁺, ret time 1.93min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.75 (s, 1H) 8.61 (s, 1H)7.97-8.11 (m, 5H) 7.79 (s, 1H) 4.69 (s, 3H) 4.21-4.25 (m, 2H) 4.01-4.04(m, 2H) 3.91 (t, J=6.26 Hz, 2H) 3.76-3.82 (m, J=3.66 Hz, 2H) 3.65-3.75(m, 10H) 2.45-2.52 (m, 2H).

Preparation of4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile

To a sealable flask containing1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.10 g, 0.20 mmol) in 1,4-dioxane (5 mL) was added tributyltin cyanide(0.07 g, 0.22 mmol) followed by Pd(PPh₃)₄ (0.07 g, 0.06 mmol). Themixture was flushed with N₂, and the tube was sealed and heated to 100°C. After 16 h of heating, the mixture was cooled to rt, and the solventwas removed in vacuo. The residue was dissolved in DMF and was filteredthrough a pad of celite to remove any remaining solids. The DMF solutionwas purified by prep HPLC to give the title compound as an off-whitesolid (0.028 g). LCMS: m/e 446.2 (M+H)⁺, ret time 1.81 min (method 2).1H NMR (500 MHz, DMSO-D₆) δ ppm 14.06 (s, 1H) 8.66 (s, 1H) 8.50 (d,J=2.14 Hz, 1H) 7.56-7.70 (m, 5H) 3.67-3.72 (m, 2H) 3.33-3.50 (m, 4H)3.13-3.17 (m, 2H).

Preparation of1-(7-acetyl-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

To a sealable flask containing1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.10 g, 0.20 mmol) in 1,4-dioxane (5 mL) was addedtributyl(1-ethoxyvinyl)tin (0.079 g, 0.22 mmol) followed by Pd(PPh₃)₄(0.07 g, 0.06 mmol). The mixture was flushed with N₂, and the tube wassealed and heated to 100° C. After 16 h of heating, the mixture wascooled to rt, and the solvent was removed in vacuo. The residue wasdissolved in DMF and was filtered through a pad of celite to remove anyremaining solids. The DMF solution was purified by prep HPLC to give thetitle compound as an off-white solid (0.025 g). LCMS: m/e 463.38 (M+H)⁺,ret time 1.88 min (method 2). 1H NMR (500 MHz, CDCl₃) δ ppm 11.02 (s,1H) 8.35 (s, 1H) 8.31 (d, J=2.75 Hz, 1H) 7.52-7.62 (m, 5H) 3.81-3.85 (m,2H) 3.61-3.65 (m, 2H) 3.39-3.43 (m, 2H) 3.31-3.35 (m, 2H) 2.80-2.83 (m,3H).

Preparation of(E)-1-(4-fluoro-7-(1-(methoxyimino)ethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

To a suspension of1-(7-acetyl-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.05 g, 0.11 mmol) in EtOH (10 mL) was added methoxylaminehydrochloride (0.05 g, 0.60 mmol). The mixture was heated to reflux for1 h, and was then cooled to rt, and concentrated in vacuo. The residuewas diluted with MeOH, and the solids that formed were collected andwashed with water. The title compound was isolated as a light-yellowsolid (0.025 g). LCMS: m/e 492.4 (M+H)⁺, ret time 2.068 min (method 2).1H NMR (500 MHz, DMSO-D₆) δ ppm 12.02 (s, 1H) 8.36 (d, J=2.14 Hz, 1H)8.27 (d, J=3.36 Hz, 1H) 7.56-7.71 (m, 5H) 4.13-4.16 (m, 3H) 3.68-3.73(m, 2H) 3.43-3.48 (m, 2H) 3.29-3.36 (m, 2H) 3.13-3.18 (m, 2H) 2.36 (s,3H).

Preparation of(E)-1-(4-fluoro-7-(1-(hydroxyimino)ethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

To a suspension of1-(7-acetyl-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.05 g, 0.11 mmol) in EtOH (10 mL) was added hydroxylaminehydrochloride (0.04 g, 0.58 mmol). The mixture was heated to reflux for1 h, and was then cooled to rt, and concentrated in vacuo. The residuewas diluted with MeOH, and the solids that formed were collected andwashed with water. The title compound was isolated as an off-white solid(0.027 g). LCMS: m/e 478.5 (M+H)⁺, ret time 1.53 min (method 1). 1H NMR(500 MHz, DMSO-D₆) δ ppm 11.95 (s, 1H) 11.61 (s, 1H) 8.34 (d, J=1.83 Hz,1H) 8.30 (d, J=3.36 Hz, 1H) 7.56-7.71 (m, 5H) 3.68-3.72 (m, 2H)3.43-3.48 (m, 2H) 3.30-3.34 (m, 2H) 3.13-3.17 (m, 2H) 2.35 (s, 3H).

Preparation of4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a sealable flask containing1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(1.0 g, 2.0 mmol) in 1,4-dioxane (20 mL) was added tributyltin cyanide(0.70 g, 2.2 mmol) followed by Pd(PPh₃)₄ (0.12 g, 0.1 mmol). The mixturewas flushed with N₂, and the tube was sealed and heated to 100° C. After20 h of heating, the mixture was cooled to rt, and was diluted with MeOH(50 mL) and was filtered through a pad of celite to remove solids. Tothe solution was added H₂O (20 mL), and the mixture was heated with aheat gun. Solids formed upon cooling, and were collected by filtration.The solids were dissolved in DMF and were purified by prep HPLC to givethe title compound as an off-white solid (30 mg). LCMS: m/e 464.11(M+H)⁺, ret time 1.095 min (method 3). 1H NMR (500 MHz, DMSO-D₆) δ ppm12.78 (s, 1H) 8.34 (d, J=2.14 Hz, 1H) 8.30 (s, 1H) 8.25 (d, J=3.36 Hz,1H) 7.88 (s, 1H) 7.56-7.71 (m, 5H) 3.67-3.72 (m, 2H) 3.43-3.47 (m, 2H)3.30-3.34 (m, 2H) 3.13-3.17 (m, 2H).

Preparation of ethyl3-(4-fluoro-3-(2-oxo-2-(4-(3-phenyl-1H-pyrazol-4-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate

To a sealable flask containing2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid(0.15 g, 0.52 mmol) in 1,4-dioxane (5 mL) was added2-(7-(5-(ethoxycarbonyl)-1H-pyrazol-3-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.24 g, 0.55 mmol) followed by Pd(PPh₃)₄ (0.18 g, 0.16 mmol). Themixture was flushed with N₂, and the tube was sealed and heated to 100°C. After 3 h of heating, the mixture was cooled to rt, and was dilutedwith MeOH. The solution was passed through a pad of celite to removesolids, and the resulting solution was concentrated under reducedpressure. The residue was dissolved in DMF, and was loaded on the prepHPLC for purification. The2-(7-(5-(ethoxycarbonyl)-1H-pyrazol-3-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid was isolated as an off-white solid (0.043 g). LCMS: m/e 347.3(M+H)⁺, ret time 1.68 min (method 2).

To a solution of2-(7-(5-(ethoxycarbonyl)-1H-pyrazol-3-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.017 g, 0.049 mmol) in DMF (1.5 mL) was added TBTU (0.017 g,0.054 mmol), diisopropylethylamine (0.15 mL), and1-(3-phenyl-1H-pyrazol-4-yl)piperazine (0.011 g, 0.049 mmol). Themixture was stirred under N₂ at rt for 14.5 h and was quenched with 10mL of H₂O. The solvent was removed under reduced pressure, and theresidue was dissolved in DMF. The DMF solution was passed though a plugof celite to remove solids, and the DMF solution was purified by prepHPLC to give the title compound as a white solid (13.3 mg). LCMS: m/e557.4 (M+H)⁺, ret time 1.79 min (method 1). 1H NMR (500 MHz, MeOD) δ ppm8.44 (s, 1H) 8.31 (d, J=2.44 Hz, 1H) 7.95 (d, J=7.32 Hz, 2H) 7.63 (s,1H) 7.56 (s, 1H) 7.46 (t, J=7.63 Hz, 2H) 7.36 (t, J=7.48 Hz, 1H) 4.46(q, J=7.22 Hz, 2H) 3.88-3.92 (m, 2H) 3.65-3.70 (m, 2H) 3.00-3.04 (m, 2H)2.91-2.95 (m, 2H) 1.45 (t, J=7.02 Hz, 3H).

Preparation of3-(4-fluoro-3-(2-oxo-2-(4-(3-phenyl-1H-pyrazol-4-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-hydroxyethyl)-1H-pyrazole-5-carboxamide.TFA

To a flask containing ethyl3-(4-fluoro-3-(2-oxo-2-(4-(3-phenyl-1H-pyrazol-4-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.025 g, 0.045 mmol) was added ethanolamine (0.5 mL). The mixture wasstirred at rt for 15.5 h, and was diluted with DMF and passed through apad of celite to remove any solids. The DMF solution was purified byprep HPLC to give the title compound as an off-white solid (0.010 g).LCMS: m/e 572.4 (M+H)⁺, ret time 1.87 min (method 2). 1H NMR (500 MHz,DMSO-D₆) δ ppm 12.23 (s, 1H) 8.67 (s, 1H) 8.36 (s, 1H) 8.28 (s, 1H)7.95-8.00 (m, 2H) 7.57-7.64 (m, 2H) 7.38-7.44 (m, 6.87 Hz, 2H) 7.28 (t,J=6.56 Hz, 1H) 3.74-3.80 (m, 2H) 3.32-3.62 (m, 7H) 2.84-2.91 (m, 2H)2.73-2.80 (m, 2H).

Preparation ofN-(3-(dimethylamino)propyl)-3-(4-fluoro-3-(2-oxo-2-(4-(3-phenyl-1H-pyrazol-4-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide.TFA

To a flask containing ethyl3-(4-fluoro-3-(2-oxo-2-(4-(3-phenyl-1H-pyrazol-4-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.043 g, 0.077 mmol) was added N1,N1-dimethylpropane-1,3-diamine (0.5mL). The mixture was stirred at rt for 113 h, and was diluted with DMFand passed through a pad of celite to remove any solids. The DMFsolution was purified by prep HPLC to give the title compound as anoff-white solid (0.03 g). LCMS: m/e 613.3 (M+H)⁺, ret time 1.91 min(method 6). 1H NMR (500 MHz, MeOD) δ ppm 8.40 (s, 1H) 8.27 (d, J=2.75Hz, 1H) 7.94 (d, J=7.32 Hz, 2H) 7.64 (s, 1H) 7.43-7.47 (m, 3H) 7.35 (t,J=7.32 Hz, 1H) 3.87-3.91 (m, 2H) 3.64-3.68 (m, 2H) 3.53 (t, J=6.41 Hz,2H) 3.24-3.29 (m, 2H) 2.99-3.03 (m, 2H) 2.95 (s, 6H) 2.90-2.94 (m, 2H)2.05-2.13 (m, 2H).

Preparation of3-(4-fluoro-3-(2-oxo-2-(4-(3-phenyl-1H-pyrazol-4-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-morpholinoethyl)-1H-pyrazole-5-carboxamide.TFA

To a flask containing ethyl3-(4-fluoro-3-(2-oxo-2-(4-(3-phenyl-1H-pyrazol-4-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate(0.038 g, 0.068 mmol) was added 2-morpholinoethanamine (0.5 mL). Themixture was stirred at rt for 113 h, and was diluted with DMF and passedthrough a pad of celite to remove any solids. The DMF solution waspurified by prep HPLC to give the title compound as an off-white solid(0.041 g). LCMS: m/e 641.6 (M+H)⁺, ret time 1.73 min (method 2). 1H NMR(500 MHz, MeOD) δ ppm 8.39 (s, 1H) 8.25-8.31 (m, 1H) 7.92-7.97 (m, 2H)7.63 (s, 1H) 7.42-7.47 (m, 3H) 7.35 (t, J=7.48 Hz, 1H) 4.07-4.16 (m, 2H)3.79-3.91 (m, 6H) 3.70-3.77 (m, 2H) 3.63-3.69 (m, 2H) 3.46-3.50 (m, 2H)3.20-3.31 (m, 2H) 2.98-3.03 (m, 2H) 2.89-2.94 (m, 2H).

Preparation of4-fluoro-N-(2-hydroxyethyl)-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a 15 mL rb flask containing1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.05 g, 0.10 mmol) was added DMF (2.0 mL), triethylamine (0.4 mL),ethanolamine (0.02 g, 0.33 mmol), and finally Pd(PPh₃)₄ (0.03 g, 0.03mmol). The flask was placed in a Parr reaction vessel equipped with apressure gauge and a gas inlet valve. The vessel was sealed and purgedwith N₂ three times, and was then purged with carbon monoxide threetimes, leaving the final fill pressure of carbon monoxide at 50 psi. Thevessel was heated to 50° C. After 15 h of heating, the mixture wascooled to rt, the carbon monoxide was removed by vacuum, and the vesselwas flushed with N₂. The mixture was concentrated under reducedpressure, and was diluted with DMF. The DMF solution was passed througha plug of celite to remove solids, and was purified by prep HPLC. Thetitle compound was recovered as an off-white solid (0.014 g). LCMS: m/e508.3 (M+H)⁺, ret time 1.35 min (method 1). 1H NMR (500 MHz, DMSO-D₆) δppm 12.85 (s, 1H) 8.82 (s, 1H) 8.36 (s, 1H) 8.28 (s, 1H) 7.56-7.71 (m,5H) 3.67-3.72 (m, 2H) 3.55-3.60 (m, 2H) 3.39-3.50 (m, 5H) 3.30-3.35 (m,2H) 3.13-3.17 (m, 2H).

Preparation of4-(dimethylamino)-N-(2-hydroxyethyl)-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide.TFA

To a 15 mL rb flask containing1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.05 g, 0.10 mmol) was added DMF (2.0 mL), triethylamine (0.4 mL),ethanolamine (0.02 g, 0.33 mmol), and finally Pd(PPh₃)₄ (0.03 g, 0.03mmol). The flask was placed in a Parr reaction vessel equipped with apressure gauge and a gas inlet valve. The vessel was sealed and purgedwith N₂ three times, and was then purged with carbon monoxide threetimes, leaving the final fill pressure of carbon monoxide at 50 psi. Thevessel was heated to 70° C. After 15 h of heating, the mixture wascooled to rt, the carbon monoxide was removed by vacuum, and the vesselwas flushed with N₂. The mixture was concentrated under reducedpressure, and was diluted with DMF. The DMF solution was passed througha plug of celite to remove solids, and was purified by prep HPLC. Thetitle compound was recovered as a yellow solid (0.020 g). LCMS: m/e533.5 (M+H)⁺, ret time 1.35 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm8.96 (s, 1H) 8.65 (s, 1H) 7.59-7.72 (m, 5H) 3.86-3.89 (m, 2H) 3.79 (t,J=5.65 Hz, 2H) 3.68-3.71 (m, 2H) 3.64 (t, J=5.65 Hz, 2H) 3.58 (s, 6H)3.40-3.44 (m, 2H) 3.30-3.35 (m, 2H).

Preparation of ethyl4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylate

To a 15 mL rb flask containing1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.10 g, 0.20 mmol) was added DMF (4.0 mL), triethylamine (0.8 mL),ethanol (0.05 g, 1.00 mmol), and finally Pd(PPh₃)₄ (0.06 g, 0.06 mmol).The flask was placed in a Parr reaction vessel equipped with a pressuregauge and a gas inlet valve. The vessel was sealed and purged with N₂three times, and was then purged with carbon monoxide three times,leaving the final fill pressure of carbon monoxide at 50 psi. The vesselwas heated to 100° C. After 6 h of heating, the mixture was cooled tort, the carbon monoxide was removed by vacuum, and the vessel wasflushed with N₂. The mixture was concentrated under reduced pressure,and was diluted with DMF. The DMF solution was passed through a plug ofcelite to remove solids, and was purified by prep HPLC. The titlecompound was recovered as an off-white solid (0.020 g). LCMS: m/e 493.4(M+H)⁺, ret time 1.82 min (method 2). 1H NMR (500 MHz, DMSO-D₆) δ ppm12.82 (s, 1H) 8.43 (s, 1H) 8.35 (d, J=3.05 Hz, 1H) 7.57-7.70 (m, 5H)4.46 (q, J=7.12 Hz, 2H) 3.67-3.72 (m, 2H) 3.43-3.47 (m, 2H) 3.31-3.35(m, 2H) 3.13-3.17 (m, 2H) 1.39 (t, J=7.17 Hz, 3H).

Preparation of 2-(1,3-dioxolan-2-yl)-4-(trimethylstannyl)thiazole

To a rb flask with an attached Dean-Stark trap containing molecularsieves, 4A (0.25 g) was added 4-bromothiazole-2-carbaldehyde (4.4 g,22.91 mmol). The starting material was dissolved in Benzene (45 ml) andEthylene glycol (1.406 ml, 25.2 mmol) was added followed by pTsOH (0.218g, 1.146 mmol). The mixture was heated to reflux for 3 h. The mixturewas cooled to rt, and was partitioned with sat. aq. NaHCO₃. The mixturewas washed 2× with sat. NaHCO₃ (40 mL), then once with sat. NaCl (40mL). The organic layer was dried with Na₂SO₄. The drying agent wasremoved by filtration, and the mixture was concentrated under reducedpressure. The residue was purified by biotage flash chromatography usinga 40+M column and a 0 to 20% EtOAc in hexanes gradient. The product,4-bromo-2-(1,3-dioxolan-2-yl)thiazole (5.1 g, 21.60 mmol, 94% yield),was collected as a light-yellow oil.

To a solution of 4-bromo-2-(1,3-dioxolan-2-yl)thiazole (5.09 g, 21.56mmol) in Toluene (100 ml) was added Hexamethylditin (10 g, 30.5 mmol)followed by Tetrakis (2.491 g, 2.156 mmol). The mixture was attached toa reflux condenser, and was flushed with N₂. The mixture was heated to100° C. for 4 h. The mixture was cooled to rt, and was loaded onto a40+M biotage cartridge that was pre-saturated with hexanes with 0.1%Et₃N. The desired product was purified using a 0-20% EtOAc in hexaneswith 0.1% Et₃N gradient. After concentrating in vacuo, the product,2-(1,3-dioxolan-2-yl)-4-(trimethylstannyl)thiazole (4.64 g, 14.50 mmol,67.3% yield), was isolated as a light-yellow oil. LCMS: m/e 322.0(M+H)⁺, ret time 2.23 min (method 7); 1H NMR (500 MHz, CDCl₃) δ ppm 7.39(s, 1H) 6.20 (s, 1H) 4.03-4.20 (m, 4H) 0.27-0.42 (m, 9H).

Preparation of1-(7-(2-(1,3-dioxolan-2-yl)thiazol-4-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

To a sealable 75 mL flask containing1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.3 g, 0.643 mmol) was added a solution of2-(1,3-dioxolan-2-yl)-4-(trimethylstannyl)thiazole (0.210 g, 0.655 mmol)in 1,4-Dioxane (10 ml). The mixture was flushed with N₂ and Pd(PPh₃)₄(0.149 g, 0.129 mmol) was added. The mixture was again flushed with N2,and the flask was sealed and heated in an oil bath to 100° C. After 20 hof heating, the mixture was cooled to rt. The mixture was transferred toa rb flask using MeOH as the transfer solvent. The solvent was removedunder reduced pressure. The residue was re-dissolved in DMF, and waspassed through a pad of celite to remove any remaining solids. The DMFsolution was purified by prep HPLC. After the prep HPLC, a mostly-puresample was collected as an off-white solid. A small portion of thismaterial was removed and re-purified by flash chromatography (0-5% MeOHin dichloromethane gradient) [20 mg after the purification]. Theremainder of the product was carried forward to the next step with noadditional purification (0.305 g). LCMS: m/e 588.1 (M+H)⁺, ret time 1.30min (method 3). 1H NMR (500 MHz, DMSO-D₆) δ ppm 12.20 (s, 1H) 8.38 (s,1H) 8.22 (s, 1H) 8.11 (s, 1H) 7.68-7.72 (m, 2H) 7.57-7.66 (m, 3H) 6.29(s, 1H) 4.16-4.20 (m, 2H) 4.07-4.10 (m, 2H) 3.99 (s, 3H) 3.67-3.71 (m,2H) 3.41-3.45 (m, 2H) 3.30-3.32 (m, 2H) 3.15-3.19 (m, 2H).

Preparation of1-(4-methoxy-7-(2-((methylamino)methyl)thiazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneTFA

To a suspension of1-(7-(2-(1,3-dioxolan-2-yl)thiazol-4-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.305 g, 0.519 mmol) in H₂O (2 mL, 111 mmol) was added TFA (1 mL, 12.98mmol). The mixture was heated to 70° C. After 18 h of heating, themixture was cooled to rt, and was stirred at rt for an additional 20 h.The mixture was concentrated under reduced pressure. The residue wasdissolved in dichloromethane and was partitioned with sat. NaHCO₃. Themixture was extracted with dichloromethane (3×10 mL) and was dried withNa₂SO₄. The drying agent was removed by filtration. The organic solutionwas concentrated under reduced pressure, and the resulting mixture waspurified by flash chromatography (0 to 5% methanol in dichloromethanegradient). The product,4-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)thiazole-2-carbaldehyde(0.103 g, 0.189 mmol, 36.5% yield) was collected as a light-yellowsolid.

To a solution of4-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)thiazole-2-carbaldehyde(0.088 g, 0.162 mmol) in DCE (3 ml) was added ACETIC ACID (9.27 μl,0.162 mmol) and 2M (in THF) methylamine (0.405 ml, 0.809 mmol). Themixture was stirred for 15 minutes at rt, and sodiumtriacetoxyborohydride was added to the mixture (0.069 g, 0.324 mmol).The mixture was stirred for 4 h at rt. An additional 0.05 g ofNa(OAc)₃BH was added, and the mixture was stirred overnight at rt. Themixture was neutralized with sat. NaHCO₃. The mixture was extracted withdichloromethane (3×10 mL), and was dried with Na₂SO₄. The drying agentwas removed by filtration, and the solution was concentrated underreduced pressure. The resulting residue was dissolved in DMF, and wasfiltered through a pad of celite to remove any solids. The DMF solutionwas purified by prep HPLC to give1-(4-methoxy-7-(2-((methylamino)methyl)thiazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione,TFA (32.6 mg, 0.048 mmol, 29.9% yield) as a light-yellow solid. LCMS:m/e 559.1 (M+H)⁺, ret time 1. 12 min (method 3). 1H NMR (500 MHz, MeOD)δ ppm 8.54-8.59 (m, 2H) 8.08 (s, 1H) 7.57-7.74 (m, 5H) 4.82 (s, 2H) 4.11(s, 3H) 3.82-3.86 (m, 2H) 3.60-3.63 (m, 2H) 3.39-3.42 (m, 2H) 3.33 (s,2H) 2.95 (s, 3H).

Preparation of1-(4-methoxy-7-(pyrimidin-4-ylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dionePreparation of1-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

Compounds1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(100 mg, 0.195 mmol), pyrimidin-5-ylboronic acid (72.6 mg, 0.586 mmol),1,1′-Bis(diphenylphosphino)ferrocene palladium (II) chloride complexwith dichloromethane (16.06 mg, 0.020 mmol) and Cesium carbonate (127mg, 0.390 mmol) were combined in Dioxane (2 mL) and Water (0.5 mL). Themixture was heated at 115° C. for 4 hours. After cooling to rt, themixture was diluted with 10 ml of MeOH and filtered. The filtration wasconcentrated and purified by HPLC to give1-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(34 mg, 0.066 mmol, 34.1% yield). LCMS: m/e 512.3 (M+H)⁺, ret time 1.04min. ¹H NMR (500 MHz, MeOD) δ ppm 9.35 (s, 1H) 9.19 (s, 2H) 8.61 (d,J=4.88 Hz, 1H) 8.49 (s, 1H) 8.20 (s, 1H) 8.05-8.11 (m, 1H) 7.83 (d,J=7.93 Hz, 1H) 7.53-7.58 (m, J=7.17, 5.34 Hz, 1H) 4.12 (s, 3H) 3.86-3.90(m, 2H) 3.63-3.68 (m, 2H) 3.43-3.55 (m, 4H).

Preparation of1-(7-(3,5-dimethylisoxazol-4-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

Compounds1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(100 mg, 0.195 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole,1,1′-Bis(diphenylphosphino)ferrocene palladium (II) chloride complexwith dichloromethane (16.06 mg, 0.020 mmol) and Cesium carbonate (127mg, 0.390 mmol) were combined in Dioxane (2 mL) and Water (0.5 mL). Themixture was heated at 115° C. for 2 hours. After cooling to rt, themixture was diluted with 10 ml of MeOH and filtered. The filtration wasconcentrated and purified by HPLC to give1-(7-(3,5-dimethylisoxazol-4-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(56 mg, 0.106 mmol, 54.3% yield). LCMS: m/e 529.3 (M+H)⁺, ret time 1.03min. ¹H NMR (500 MHz, MeOD) δ ppm 8.65 (s, 1H) 8.62-8.64 (m, J=4.88 Hz,1H) 8.23 (s, 1H) 8.08-8.13 (m, 1H) 7.84 (d, J=8.24 Hz, 1H) 7.55-7.60 (m,J=6.71, 4.88 Hz, 1H) 4.15 (s, 3H) 3.87-3.90 (m, 2H) 3.66-3.69 (m, 2H)3.44-3.54 (m, 4H) 2.41 (s, 3H) 2.22 (s, 3H).

Preparation of1-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

To a suspension of2-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (50 mg, 0.168 mmol), 1-(1-phenyl-1H-tetrazol-5-yl)piperazinehydrochloride (40.2 mg, 0.151 mmol) and2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(59.2 mg, 0.184 mmol) in DMF (1 ml) was added N,N-Diisopropylethylamine(0.146 ml, 0.838 mmol). The mixture was stirred at room temperature for4 hours. The mixture was diluted with 150 ml of CH₂Cl₂ and washed with5% NaHCO₃ (30 ml), brine (30 ml). The organic layer was dried overNa₂SO₄ and concentrated to give a residue, which was purified by prep.HPLC to give1-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(10 mg, 0.020 mmol, 11.68% yield) (light tan solid). LCMS: m/e 511.4(M+H)⁺, ret time 1.25 min. ¹H NMR (500 MHz, MeOD) δ ppm 9.30 (s, 1H)9.17 (s, 2H) 8.38 (s, 1H) 8.16 (s, 1H) 7.58-7.65 (m, 5H) 4.09 (s, 3H)3.80-3.83 (m, 2H) 3.57-3.60 (m, 2H) 3.38-3.42 (m, 2H) 3.31-3.33 (m, 2H).

Preparation ofN-(2-hydroxyethyl)-4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a stainless steel pressure vessel containing1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.16 g, 0.343 mmol) in Dioxane (10 mL) was added triethylamine (0.7 mL,5.02 mmol), water (0.05 mL), ethanolamine (0.021 mL, 0.343 mmol), andtetrakis (0.079 g, 0.069 mmol). The mixture was flushed with N₂. Thestainless steel pressure vessel was purged of air, and refilled with N₂three times. After the final fill with N₂, the N₂ was removed by vacuum.The vessel was filled and purged with 50 psi carbon monoxide threetimes, then filled the vessel to an initial reaction pressure of 90 psiof carbon monoxide. The vessel was heated in an oil bath at 100° C.After 16 h, the mixture was cooled to 0° C. The excess CO was removed byvacuum, and the mixture was diluted with MeOH and was transferred to aflask. The mixture was concentrated under reduced pressure. The residuewas taken up in DMF, and was filtered through a pad of celite to removeany solids. The DMF solution was purified by prep HPLC. After the firstpurification, the product was purified a second time using a biotage25+M cartridge and a 0-5% MeOH in dichloromethane as the gradient. Theproduct,N-(2-hydroxyethyl)-4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.074 g, 0.142 mmol, 41.6% yield), was isolated as a white solid. ¹HNMR (500 MHz, DMSO-D6) δ ppm 12.53 (s, 1H) 8.66 (s, 1H) 8.12 (s, 1H)8.07 (s, 1H) 7.56-7.72 (m, 5H) 4.83 (t, J=5.49 Hz, 1H) 4.02 (s, 3H)3.66-3.70 (m, 2H) 3.57 (q, J=5.90 Hz, 2H) 3.39-3.46 (m, 4H) 3.28-3.32(m, 2H) 3.17 (d, J=3.36 Hz, 2H). LCMS: m/e 520.32 (M+H)⁺, ret time 2.165min (method 4).

Preparation of4-methoxy-N-methyl-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a stainless steel pressure vessel containing1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.1 g, 0.21 mmol) in Dioxane (4 mL) was added triethylamine (0.5 mL,3.59 mmol), water (0.05 mL), methylamine (2M in THF) (0.86 mL, 1.7mmol), and tetrakis (0.050 g, 0.043 mmol). The mixture was flushed withN₂. The stainless steel pressure vessel was purged of air, and refilledwith N₂ three times. After the final fill with N₂, the N₂ was removed byvacuum. The vessel was filled and purged with 50 psi carbon monoxidethree times, then filled the vessel to an initial reaction pressure of90 psi of carbon monoxide. The vessel was heated in an oil bath at 100°C. After 14 h, the mixture was cooled to 0° C. The excess CO was removedby vacuum, and the mixture was diluted with MeOH and was transferred toa flask. The mixture was concentrated under reduced pressure, and theresulting residue was taken up in DMF. The DMF mixture was passedthrough a pad of celite to remove solids. The DMF solution was thenpurified by prep HPLC. The desired product,4-methoxy-N-methyl-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide,TFA (0.066 g, 0.109 mmol, 51.1% yield), was isolated as a light-yellowsolid. ¹H NMR (500 MHz, CHLOROFORM-D) δ ppm 11.55 (s, 1H) 8.56-8.60 (m,1H) 8.34 (s, 1H) 7.99 (s, 1H) 7.52-7.60 (m, 5H) 4.09 (s, 3H) 3.79-3.84(m, 2H) 3.55-3.59 (m, 2H) 3.38-3.42 (m, 2H) 3.32-3.35 (m, 2H) 3.05 (d,J=4.88 Hz, 3H). LCMS: m/e 490.36 (M+H)⁺, ret time 2.262 min (method 4).

Preparation ofN-cyclopropyl-4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a stainless steel pressure vessel containing1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.076 g, 0.162 mmol) in Dioxane (4 mL) was added triethylamine (0.5 mL,3.59 mmol), water (0.05 mL), cyclopropylamine (0.034 mL, 0.487 mmol),and tetrakis (0.038 g, 0.032 mmol). The mixture was flushed with N₂. Thestainless steel pressure vessel was purged of air, and refilled with N₂three times. After the final fill with N₂, the N₂ was removed by vacuum.The vessel was filled and purged with 50 psi carbon monoxide threetimes, then filled the vessel to an initial reaction pressure of 90 psiof carbon monoxide. The vessel was heated in an oil bath at 100° C.After 15 h, the mixture was cooled to 0° C. The excess CO was removed byvacuum, and the mixture was diluted with MeOH and was filtered through apad of celite to remove the solids. The product was purified by prepHPLC to giveN-cyclopropyl-4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.014 g, 0.027 mmol, 16.7% yield) as an off-white solid. ¹H NMR (500MHz, DMSO-D6) δ ppm 12.54 (s, 1H) 8.77 (s, 1H) 8.63-8.68 (m, 1H)8.12-8.19 (m, 2H) 8.02 (s, 1H) 7.84 (d, J=7.93 Hz, 1H) 7.64 (dd, J=7.48,4.73 Hz, 1H) 4.01 (s, 3H) 3.68-3.73 (m, 2H) 3.38-3.45 (m, 4H) 3.22-3.27(m, 2H) 2.92-2.99 (m, 1H) 0.69-0.74 (m, 4H). LCMS: m/e 517.18 (M+H)⁺,ret time 1.378 min (method 3).

The following tertiary alcohol intermediates were formed by thestandardized reaction that follows.

Preparation of 2-(3-(tributylstannyl)-1H-pyrazol-5-yl)propan-2-ol, and3-(3-(tributylstannyl)-1H-pyrazol-5-yl)pentan-3-ol

To a solution of ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate(0.1-0.25 g) in tetrahydrofuran was added the grignard reagent (4 equiv)dropwise. The mixture was stirred at rt for 2.5 h, and was carefullyquenched with water. The mixture was extracted with EtOAc (3×30 mL),washed with brine (30 mL), and dried with MgSO₄. The drying agent wasremoved by filtration, and the organic solution was concentrated underreduced pressure. The product was isolated as an oil and was used withno further purification. LCMS: m/e 417.00 (M+H)⁺, ret time 3.618 min(method 9) for 2-(3-(tributylstannyl)-1H-pyrazol-5-yl)propan-2-ol; LCMS:m/e 445.08 (M+H)⁺, ret time 4.063 min (method 9) for3-(3-(tributylstannyl)-1H-pyrazol-5-yl)pentan-3-ol.

The general procedure for coupling of tin reagents to the either the1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dionecore or the1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dionecore was applied to the following compounds.

General Tin Coupling Procedure

1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneor1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.05-2 g) was weighed into a sealable flask. The tin reagent (1-1.25equiv) was added, and the mixture was diluted with 1,4-dioxane (0.02-0.2molar solution). To the mixture was addedtetrakis(triphenylphosphine)palladium(0) (0.2 equivalents) and themixture was flushed with N₂, sealed, and heated to 100° C. After heatingfor 14-24 h, The mixture was cooled to rt, and was transferred to aflask using MeOH and dichloromethane as the wash solvents. The solutionwas concentrated and the residue was purified using either the prep HPLCor biotage flash chromatography.

Preparation of1-(7-(5-(hydroxymethyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione)using the general tin coupling procedure

1-(7-(5-(hydroxymethyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(54 mg, 0.102 mmol, 23.86% yield), white solid. ¹H NMR (500 MHz,DMSO-D6) δ ppm 13.09 (s, 1H) 12.02 (s, 1H) 8.65-8.68 (m, 1H) 8.13-8.19(m, 2H) 8.06 (s, 1H) 7.85 (d, J=8.24 Hz, 1H) 7.63 (dd, J=7.32, 4.88 Hz,1H) 6.79 (s, 1H) 5.38 (t, J=5.65 Hz, 1H) 4.60 (d, J=5.49 Hz, 2H) 3.96(s, 3H) 3.69-3.73 (m, 2H) 3.39-3.46 (m, 4H) 3.23-3.27 (m, 2H). LCMS: m/e530.36 (M+H)⁺, ret time 1.742 min (method 4).

Preparation of1-(7-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneusing the general tin coupling procedure

1-(7-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione,TFA (48 mg, 0.071 mmol, 20.52% yield), an off-white solid. ¹H NMR (500MHz, DMSO-D6) δ ppm 12.43 (s, 1H) 8.67 (dd, J=4.88, 1.22 Hz, 1H) 8.39(s, 1H) 8.14-8.18 (m, 1H) 8.04 (s, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd,J=6.87, 5.34 Hz, 1H) 6.93 (s, 1H) 4.01 (s, 3H) 3.70-3.74 (m, 2H)3.40-3.49 (m, 4H) 3.25-3.29 (m, 2H) 1.55 (s, 6H). LCMS: m/e 558.43(M+H)⁺, ret time 1.905 min (method 4).

Preparation of1-(4-methoxy-7-(2-methoxythiazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneUsing the General Tin Coupling Procedure

1-(4-methoxy-7-(2-methoxythiazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.014 g, 0.026 mmol, 15.98% yield) was isolated as a light-yellowsolid. ¹H NMR (500 MHz, CHLOROFORM-D) δ ppm 11.31 (s, 1H) 8.57-8.60 (m,1H) 8.18 (s, 1H) 7.94-7.99 (m, 2H) 7.84 (d, J=8.24 Hz, 1H) 7.69 (s, 1H)7.43 (dd, J=7.63, 4.88 Hz, 1H) 4.21 (s, 3H) 4.04 (s, 3H) 3.89-3.92 (m,2H) 3.64-3.68 (m, 2H) 3.56-3.60 (m, 2H) 3.47-3.51 (m, 2H). LCMS: m/e547.35 (M+H)⁺, ret time 2.053 min (method 4).

Preparation of1-(4-methoxy-7-(thiazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneUsing the General Tin Coupling Procedure

1-(4-methoxy-7-(thiazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione,TFA (7.6 mg, 0.012 mmol, 7.52% yield), was isolated as an off-white ¹HNMR (500 MHz, CHLOROFORM-D) δ ppm 12.18 (s, 1H) 9.44 (s, 1H) 9.08 (d,J=1.83 Hz, 1H) 8.61 (d, J=4.88 Hz, 1H) 8.54 (s, 1H) 8.30 (s, 1H)7.97-8.02 (m, 1H) 7.88 (d, J=8.24 Hz, 1H) 7.44-7.49 (m, 1H) 4.15 (s, 3H)3.90-3.94 (m, 2H) 3.71-3.76 (m, 2H) 3.56-3.62 (m, 4H). LCMS: m/e 517.35(M+H)⁺, ret time 1.810 min (method 4).

Preparation of1-(4-methoxy-7-(thiazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneUsing the General Tin Coupling Procedure

1-(4-methoxy-7-(thiazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione,TFA (7.6 mg, 0.012 mmol, 7.5% yield), was isolated as an off-whitesolid. ¹H NMR (500 MHz, DMSO-D6) δ 12.76 (s, 1H) 9.20 (s, 1H) 8.66-8.69(m, 1H) 8.63 (s, 1H) 8.34 (d, J=3.05 Hz, 1H) 8.13-8.19 (m, 1H) 8.11 (s,1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd, J=6.41, 4.88 Hz, 1H) 3.98 (s, 3H)3.69-3.74 (m, 2H) 3.41-3.62 (m, 4H) 3.25-3.29 (m, 2H). LCMS: m/e 517.40(M+H)⁺, ret time 1.858 min (method 4).

Preparation of1-(4-methoxy-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneUsing the General Tin Coupling Procedure

1-(4-methoxy-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione,TFA (0.09 g, 0.147 mmol, 24.89% yield) was isolated as a white solid. ¹HNMR (500 MHz, DMSO-D6) δ ppm 12.49 (s, 1H) 8.67 (dd, J=4.88, 1.22 Hz,1H) 8.35 (s, 1H) 8.12-8.19 (m, 1H) 8.06 (s, 1H) 8.01 (d, J=2.14 Hz, 1H)7.85 (d, J=8.24 Hz, 1H) 7.64 (dd, J=7.17, 5.34 Hz, 1H) 7.08 (s, 1H) 4.01(s, 3H) 3.70-3.75 (m, 2H) 3.40-3.49 (m, 4H) 3.25-3.30 (m, 2H). LCMS: m/e500.4 (M+H)⁺, ret time 1.767 min (method 4).

Preparation of1-(4-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-1-yl)piperazin-1-yl)ethane-1,2-dione

To a solution of1-(4-methoxy-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.069 g, 0.138 mmol) in DMF (3 mL) was added NaH (0.055 g, 1.381 mmol).The mixture was stirred for ten minutes and MeI (0.017 mL, 0.276 mmol)was added. After being stirred for 45 minutes, the mixture was quenchedwith water. The mixture was concentrated under reduced pressure. Theresulting residue was diluted with DMF and was passed through a plug ofcotton to remove solids. The DMF solution was purified by prep HPLC togive1-(4-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneas a light-yellow solid (0.017 g, 0.033 mmol, 33.1% yield). ¹H NMR (500MHz, DMSO-D6) δ ppm 12.37 (s, 1H) 8.67 (dd, J=4.88, 1.22 Hz, 1H) 8.33(s, 1H) 8.13-8.18 (m, 1H) 8.05 (s, 1H) 7.93 (d, J=2.14 Hz, 1H) 7.85 (d,J=7.93 Hz, 1H) 7.64 (dd, J=7.48, 4.73 Hz, 1H) 6.99 (s, 1H) 4.05 (s, 3H)4.00 (s, 3H) 3.70-3.74 (m, 2H) 3.40-3.48 (m, 4H) 3.24-3.29 (m, 2H).LCMS: m/e 514.38 (M+H)⁺, ret time 1.820 min (method 1).

Preparation of2-(7-(1-(carboxymethyl)-1H-pyrazol-3-yl)-4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)aceticacid and2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)aceticacid

To a solution of1-(4-methoxy-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.207 g, 0.414 mmol) in DMF (2 mL) was added NaH (0.083 g, 2.072 mmol).The mixture was stirred for 5 minutes at rt and methyl bromoacetate(0.047 mL, 0.497 mmol) was added. The mixture was stirred at rt for 30minutes. LC/MS showed starting material still present, so an additional0.05 mL of methyl bromoacetate was added. The mixture was stirred for 1h at rt, and was quenched with water. The solvent was removed underreduced pressure, and the residue was partitioned with water anddichloromethane. The aqueous layer was acidified to pH=1 using 0.1N HCl.The solids that formed were collected by filtration, dissolved in DMF,and were purified by prep HPLC. The aqueous layer containing theremainder of the material was concentrated under reduced pressure, andwas dissolved in DMF. The DMF solution was filtered through a plug ofcelite to remove solids, and the DMF solution was purified by prep HPLC.A second prep HPLC run was used to purify the product.2-(7-(1-(carboxymethyl)-1H-pyrazol-3-yl)-4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)aceticacid was isolated as a light-yellow solid (0.032 g, 0.052 mmol, 12.5%yield). ¹H NMR (500 MHz, DMSO-D6) δ ppm 8.65-8.69 (m, 1H) 8.50 (s, 1H)8.13-8.19 (m, 2H) 7.92 (s, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd, J=7.63,4.88 Hz, 1H) 6.65 (s, 1H) 5.17 (s, 2H) 5.05 (s, 2H) 4.01 (s, 3H) 3.72(s, 2H) 3.45 (dd, J=11.60, 3.05 Hz, 4H) 3.29 (d, J=3.36 Hz, 2H). LCMS:m/e 616.34 (M+H)⁺, ret time 1.565 min (method 4).2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)aceticacid was isolated as an off-white solid (0.132 g, 0.237 mmol, 52.1%yield). ¹H NMR (500 MHz, DMSO-D6) δ ppm ¹H NMR (500 MHz, DMSO-D6) d ppm12.37 (s, 1H) 8.65-8.68 (m, 1H) 8.32 (s, 1H) 8.13-8.18 (m, 1H) 8.07 (s,1H) 7.96 (d, J=2.44 Hz, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd, J=7.48,4.73 Hz, 1H) 7.03 (d, J=1.83 Hz, 1H) 5.17-5.20 (m, 2H) 4.01 (s, 3H)3.70-3.75 (m, 2H) 3.40-3.49 (m, 4H) 3.24-3.29 (m, 2H). LCMS: m/e 558.19(M+H)⁺, ret time 0.955 min (method 3).

Preparation of2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide

To a sealable vial containing a mixture of2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)aceticacid (0.05 g, 0.090 mmol) in DMF (4 mL) was added Hunig's Base (0.157mL, 0.897 mmol), o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (0.043 g, 0.135 mmol), and dimethylamine (0.224 mL,0.448 mmol). The vial containing the mixture was sealed and stirred atrt for 16 h. The mixture was quenched with water and stripped of solventunder reduced pressure. The resulting residue was taken up in DMF andfiltered through a plug of cotton. The DMF solution was purified usingthe prep HPLC. A second prep HPLC was run for purification. The product,2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide,TFA (32 mg, 0.046 mmol, 51.1% yield), was isolated as an off whitesolid. ¹H NMR (500 MHz, DMSO-D6) δ ppm 12.45 (s, 1H) 8.67 (d, J=3.66 Hz,1H) 8.38 (s, 1H) 8.13-8.19 (m, 1H) 8.06 (s, 1H) 7.83-7.91 (m, 2H) 7.64(dd, J=6.71, 4.88 Hz, 1H) 7.08 (s, 1H) 5.35 (s, 2H) 4.02 (s, 3H)3.69-3.75 (m, 2H) 3.40-3.50 (m, 4H) 3.24-3.30 (m, 2H) 3.10 (s, 3H) 2.89(s, 3H). LCMS: m/e 585.39 (M+H)⁺, ret time 1.760 min (method 4).

Preparation of2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)-N-methylacetamide

To a sealable vial containing a solution of2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)aceticacid (60 mg, 0.108 mmol) in DMF (4 mL) was addedo-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (51.8mg, 0.161 mmol), Hunig's Base (0.188 mL, 1.076 mmol), and methylamine(0.538 mL, 1.076 mmol). The mixture was sealed in a vial, and wasstirred for 14.5 h at rt. The mixture was quenched with water andstripped of solvent under reduced pressure. The resulting residue wastaken up in DMF and filtered through a plug of cotton. The DMF solutionwas purified using prep HPLC.2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)-N-methylacetamide,TFA (0.032 g, 0.047 mmol, 43.4% yield) was isolated as an off-whitesolid. ¹H NMR (500 MHz, DMSO-D6) δ ppm 12.36 (s, 1H) 8.67 (dd, J=4.88,1.22 Hz, 1H) 8.35 (s, 1H) 8.13-8.19 (m, 1H) 8.01-8.09 (m, 2H) 7.94 (d,J=2.14 Hz, 1H) 7.85 (d, J=7.94 Hz, 1H) 7.64 (dd, J=7.63, 4.88 Hz, 1H)7.04 (s, 1H) 5.02 (s, 2H) 3.99-4.03 (m, 3H) 3.70-3.75 (m, 2H) 3.40-3.50(m, 4H) 3.24-3.29 (m, 2H) 2.65 (d, J=4.58 Hz, 3H). LCMS: m/e 571.44(M+H)⁺, ret time 1.742 min (method 4).

Preparation of intermediate2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid

To a sealable flask containing methyl2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (0.070g, 0.262 mmol) and 3-(3-(tributylstannyl)-1H-pyrazol-5-yl)pentan-3-ol(0.116 g, 0.262 mmol) was added tetrakis(triphenylphosphine)palladium(0)(0.060 g, 0.052 mmol). 1,4-Dioxane (5 ml) was added and the mixture wasflushed with N₂. The tube was sealed, and the mixture was heated to 115°C. After 16 h of heating, the mixture was cooled to rt and the solventwas removed under reduced pressure. The residue was diluted with MeOHand was filtered through a pad of celite to remove any solids. Thesolution was concentrated again under reduced pressure and the residuewas dissolved in DMF and was purified by prep HPLC to give the product,methyl2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate(0.073 g, 0.189 mmol, 72.2% yield) as an off-white solid. LCMS: m/e387.19 (M+H)⁺, ret time 1.075 min (method 3).

To a flask containing methyl2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate(0.066 g, 0.171 mmol) was added MeOH (1 mL) and Water (1 mL). To themixture was added potassium carbonate (0.118 g, 0.854 mmol). After 1 h,the mixture was made acidic (pH=1) by adding 1N HCl. No precipitateformed, so the solvent was removed under reduced pressure. The crudemixture containing2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid was carried forward to the next step with no further purification.LCMS: m/e 373.22 (M+H)⁺, ret time 1.723 min (method 4).

Preparation1-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

To a flask containing a solution of2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.06 g, 0.16 mmol) in DMF (5 ml) was added Hunig's Base (1.1 ml,6.30 mmol), 1-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazine (0.043 g,0.188 mmol) and TBTU (0.121 g, 0.376 mmol). The flask was flushed withN₂, and was stirred at rt. for 24 h. The mixture was quenched withwater. The solvent was removed under reduced pressure, and the resultingresidue was taken up in DMF. The DMF solution was filtered through a padof celite to remove any solids, and was purified by prep HPLC to give,1-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione,TFA (0.015 g, 0.021 mmol, 13% yield) as an off-white solid. ¹H NMR (500MHz, DMSO-D6) δ ppm 13.19 (s, 1H) 12.37 (s, 1H) 8.65-8.68 (m, 1H) 8.38(s, 1H) 8.13-8.18 (m, 1H) 8.03 (s, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd,J=7.02, 5.19 Hz, 1H) 6.87 (s, 1H) 4.01 (s, 3H) 3.70-3.74 (m, 2H)3.44-3.48 (m, 2H) 3.40-3.44 (m, 2H) 3.25-3.29 (m, 2H) 1.76-1.86 (m, 4H)0.79 (t, J=7.32 Hz, 6H). LCMS: m/e 586.55 (M+H)⁺, ret time 2.102 min(method 4).

Preparation of intermediate2-(7-(4-chloro-1H-pyrazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid

To a sealable flask containing7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridine (1 g, 4.40 mmol) was added4-chloro-1H-pyrazole (0.903 g, 8.81 mmol), potassium carbonate (2.435 g,17.62 mmol), copper(I) iodide (0.419 g, 2.202 mmol), andtrans-1,2-bis(methylamino)cyclohexane (0.626 g, 4.40 mmol). The mixturewas diluted with 1,4-Dioxane (15 mL) and was sealed and heated to 100°C. for 3 h. The mixture was cooled to rt and was filtered through a padof celite to remove any solids. The organic solution as concentratedunder reduced pressure, and the residue was purified by flashchromatography to give7-(4-chloro-1H-pyrazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridine (0.79g, 3.18 mmol, 72.1% yield) as an off-white solid. LCMS: m/e 249.12(M+H)⁺, ret time 2.851 min (method 4).

To sealable flask containing7-(4-chloro-1H-pyrazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridine (0.785g, 3.16 mmol) in dichloromethane (35 mL) was added nitromethane (3.5 mL,64.9 mmol) and aluminum chloride (2.53 g, 18.94 mmol). The mixture wasstirred for 5 minutes and methyl oxalyl chloride (0.872 mL, 9.47 mmol)was added.

The mixture was sealed and heated to 50° C. for 6 h. The mixture wascooled to rt and stirred overnight. The mixture was quenched carefullywith water and the solids that formed were collected by filtration andwere washed with water.2-(7-(4-chloro-1H-pyrazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.45 g, 1.403 mmol, 44.5% yield), was isolated as an orange solid.LCMS: m/e 321.14 (M+H)⁺, ret time 2.523 min (method 4).

Preparation1-(7-(4-chloro-1H-pyrazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

A solution of2-(7-(4-chloro-1H-pyrazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.449 g, 1.4 mmol) in DMF (15 mL) was added to a flask containing1-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazine, HCl (0.402 g, 1.5mmol). To the mixture was added Hunig's Base (2.445 mL, 14.00 mmol)followed by o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (0.562 g, 1.750 mmol). The mixture was stirred at rtfor 78 h and was quenched with water. The solids that formed werecollected by filtration and were washed with water. The solids had someimpurities, so they were purified further by prep HPLC. The motherliquor was concentrated under reduced pressure and was purified by flashchromatography. The combined purified fractions gave1-(7-(4-chloro-1H-pyrazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.42 g, 0.787 mmol, 56.2% yield) as an off-white solid. ¹H NMR (500MHz, DMSO-D6) δ 12.48 (s, 1H) 8.85 (s, 1H) 8.67 (d, J=3.05 Hz, 1H)8.13-8.21 (m, 2H) 8.09 (s, 1H) 7.82-7.89 (m, 2H) 7.64 (dd, J=7.63, 4.88Hz, 1H) 3.97 (s, 3H) 3.69-3.74 (m, 2H) 3.38-3.49 (m, 4H) 3.23-3.28 (m,2H). LCMS: m/e 534.30 (M+H)⁺, ret time 2.696 min (method 4).

Preparation ofN-(1-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide

Step-1

To a mixture of 1H-1,2,4-triazol-3-amine (500 mg, 5.95 mmol) and TEA(0.829 mL, 5.95 mmol) in toluene (25 mL) was added pivaloyl chloride(0.732 mL, 5.95 mmol). The mixture was heated up at 110° C. for 13 h.The reaction mixture was quenched with water, filtered and the extractedwith ethyl acetate (3×10 ml). The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure toafford N-(1H-1,2,4-triazol-3-yl)pivalamide (250 mg, 25%) as white solid.1H NMR (500 MHz, MeOD) δ ppm 1.48 (s, 9H) 7.48 (s, 1H).

Step-2

A mixture of 7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridine (250 mg, 1.101mmol), potassium carbonate (457 mg, 3.30 mmol), copper(I) iodide (105mg, 0.551 mmol), N-(1H-1,2,4-triazol-3-yl)pivalamide and(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (78 mg, 0.551 mmol) in1,4-dioxane (2 mL) were heated up at 110° C. for 13 h. The reactionmixture was filtered through a silica gel pad and concentrated underreduced pressure. The resulting crude was purified by prep HPLC to giveN-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide(90 mg, 26%) as pale yellow oil. LCMS: m/e 315.05 (M+H)⁺, ret time 1.55min (method 8).

Step-3

To an oven-dried flask in ice bath was added AlCl₃ (382 mg, 2.86 mmol),then CH₂Cl₂ (4 mL) was introduced at 0° C. Nitromethane (10.84 μL, 0.201mmol) was added at that temperature. Ice bath was removed and themixture was stirred at room temperature for 30 min.N-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide(90 mg, 0.286 mmol) and methyl 2-chloro-2-oxoacetate (0.079 mL, 0.859mmol) were added at 0° C. The reaction mixture was stirred for threehours at room temperature. The reaction mixture was quenched withammonium acetate (8 mL) and extracted with ethyl acetate (3×10 mL). Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure to afford methyl2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate(40 mg, 45%) as white solid.

To a mixture of methyl2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate(40 mg, 0.100 mmol) in water (1 mL) and MeOH (1 mL) was added K₂CO₃ (83mg, 0.599 mmol) at room temperature. The reaction mixture was stirredovernight at room temperature. MeOH was removed under reduced pressure.The water layer was acidified to PH=5-6 using 1N HCl and concentratedunder reduced pressure. The resulting residue was washed with water,filtered and dried to give2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (30 mg, 78%) as white solid. LCMS: m/e 387.18 (M+H)⁺, ret time 2.46min (method 4).

Step-4

A mixture of2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (15 mg, 0.039 mmol),4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-ium chloride (11.43 mg,0.043 mmol), 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (13.71 mg, 0.043 mmol) and N,N-diisopropyl ethylamine(0.022 ml, 0.124 mmol) in DMF (1 ml) was stirred overnight at roomtemperature. The reaction mixture was filtered through a silica gel padand concentrated under reduced pressure. The resulting crude waspurified by prep HPLC to giveN-(1-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide(10 mg, 43%) as white solid. LCMS: m/e 600.47 (M+H)⁺, ret time 2.67 min(method 4). ¹H NMR (500 MHz, DMSO-D6) δ ppm 1.22 (s, 9H) 3.23-3.29 (m,2H) 3.39-3.49 (m, 4H) 3.68-3.74 (m, 2H) 3.99 (s, 3H) 7.64 (dd, J=7.63,4.88 Hz, 1H) 7.85 (d, J=8.24 Hz, 1H) 7.88 (s, 1H) 8.13-8.18 (m, 1H) 8.21(s, 1H) 8.23 (d, J=3.66 Hz, 1H) 8.64-8.69 (m, 1H) 11.36 (s, 1H) 12.59(d, J=3.36 Hz, 1H)

Preparation of4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate,1-(4-methoxy-7-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneand isopropyl4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate

Step-1

A mixture of1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(300 mg, 0.586 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(250 mg, 0.644 mmol), Na₂CO₃ (310 mg, 2.93 mmol) and PdCl₂(dppf)₂-CH₂Cl₂adduct (47.8 mg, 0.059 mmol) in water (1.000 mL) and 1,4-dioxane (1 mL)was heated up at 80° C. for 2 h. The reaction mixture was cooled to roomtemperature, filtered through a silica gel pad and concentrated underreduced pressure. The resulting crude was purified by prep HPLC to givetert-butyl4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate(250 mg, 62%) as white solid. LCMS: m/e 694.36 (M+H)⁺, ret time 1.68 min(method 8). ¹H NMR (500 MHz, MeOD) δ ppm 1.52 (s, 9H) 3.41-3.46 (m, 4H)3.47-3.51 (m, 2H) 3.52-3.56 (m, 2H) 3.64 (m, 4H) 3.69-3.75 (m, 2H)3.86-3.95 (m, 2H) 4.17 (s, 3H) 7.28 (d, J=8.54 Hz, 2H) 7.63 (dd, J=7.63,4.88 Hz, 1H) 7.77 (d, J=8.55 Hz, 2H) 7.90 (d, J=8.24 Hz, 1H) 8.00 (s,1H) 8.17 (t, J=7.78 Hz, 1H) 8.68 (s, 2H)

Step-2

To a solution of tert-butyl4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate(250 mg, 0.360 mmol) in 1,4-dioxane (2 mL) was added 4N HCl in1,4-dioxane (0.450 mL, 1.802 mmol) at room temperature, the mixture wasstirred for 2 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure. The resulting crude was purified byprep HPLC to give1-(4-methoxy-7-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(200 mg, 93%) as white solid. LCMS: m/e 594.55 (M+H)⁺, ret time 1.76 min(method 4). ¹H NMR (500 MHz, MeOD) δ ppm 3.42-3.48 (m, 4H) 3.50 (m, 2H)3.54 (m, 2H) 3.64-3.70 (m, 4H) 3.71 (m, 2H) 3.90 (m, 2H) 4.16 (s, 3H)7.36 (d, J=8.54 Hz, 2H) 7.63 (dd, J=7.17, 5.04 Hz, 1H) 7.82 (d, J=8.85Hz, 2H) 7.90 (d, J=8.24 Hz, 1H) 8.04 (s, 1H) 8.17 (t, J=7.63 Hz, 1H)8.63-8.75 (m, 2H).

Step-3

To a solution of1-(4-methoxy-7-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(50 mg, 0.084 mmol) in THF (1 mL) and DMF (1 mL) were added TEA (0.023mL, 0.168 mmol) and isopropyl carbonochloridate (13.42 mg, 0.109 mmol)at room temperature. The reaction was stirred for 3 hours. The reactionmixture was concentrated under reduced pressure. The resulting crude waspurified by prep HPLC to give isopropyl4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate(20 mg, 35%) as white solid. LCMS: m/e 680.58 (M+H)⁺, ret time 2.49 min(method 4). ¹H NMR (500 MHz, MeOD) δ ppm 1.30 (d, J=6.10 Hz, 6H)3.41-3.50 (m, 6H) 3.50-3.58 (m, 2H) 3.65-3.75 (m, 6H) 3.86-3.93 (m, 2H)4.14 (s, 3H) 4.95-4.99 (m, 1H) 7.28 (d, J=8.85 Hz, 2H) 7.63 (dd, J=7.32,4.88 Hz, 1H) 7.77 (d, J=8.55 Hz, 2H) 7.89 (d, J=7.93 Hz, 1H) 8.01 (s,1H) 8.12-8.20 (m, 1H) 8.67 (s, 2H).

The following compounds were prepared in the same manner from1-(4-methoxy-7-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneand the corresponding acylating agent.

LC/MS (M + H)⁺ Structure Name RT (min) NMR

isobutyl 4-(4- (4-methoxy-3- 2-oxo-2-(4- (1-(pyridin-2- yl)-1H-tetrazol-5- yl)piperazin- 1-yl)acetyl)- 1H- pyrrolo[2,3- c]pyridin-7-yl)phenyl) piperazine-1- carboxylate 694.66 2.64 (Method 4) ¹H NMR (500MHz, MeOD) δ ppm 0.95- 1.08 (m, 6H) 1.91-2.08 (m, 1H) 3.42-3.50 (m, 6H)3.50-3.57 (m, 2H) 3.70 (s, 6H) 3.86-3.91 (m, 2H) 3.93 (d, J = 6.41 Hz,2H) 4.14 (s, 3H) 7.27 (d, J = 8.85 Hz, 2H) 7.62 (dd, J = 6.71, 4.88 Hz,1H) 7.76 (d, J = 8.85 Hz, 2H) 7.89 (d, J = 7.93 Hz, 1H) 8.01 (s, 1H)8.11-8.21 (m, 1H) 8.64- 8.72 (m, 2H)

ethyl 4-(4-(4- methoxy-3-(2- oxo-2-(4-(1- (pyridin-2-yl)- 1H-tetrazol-5-yl)piperazin- 1-yl)acetyl)- 1H- pyrrolo[2,3- c]pyridin-7- yl)phenyl)piperazine-1- carboxylate 666.62 2.38 (Method 4) ¹H NMR (500 MHz, MeOD)δ ppm 1.32 (t, J = 7.17 Hz, 3H) 3.42- 3.51 (m, 6H) 3.51-3.57 (m, 2H)3.64-3.75 (m, 6H) 3.86-3.94 (m, 2H) 4.15 (s, 3H) 4.20 (q, J = 7.02 Hz,2H) 7.28 (d, J = 9.16 Hz, 2H) 7.63 (dd, J = 7.63, 4.88 Hz, 1H) 7.77 (d,J = 8.85 Hz, 2H) 7.89 (d, J = 8.24 Hz, 1H) 8.01 (s, 1H) 8.13- 8.21 (m,1H) 8.64-8.72 (m, 2H)

N-tert-butyl- 4-(4-(4- methoxy-3-(2- oxo-2-(4-(1- (pyridin-2-yl)-1H-tetrazol-5- yl)piperazin- 1-yl)acetyl)- 1H- pyrrolo[2,3- c]pyridin-7-yl)phenyl) piperazine-1- carboxamide 693.73 2.36 (Method 4) ¹H NMR (500MHz, MeOD) δ ppm 1.38 (s, 9H) 3.43-3.47 (m, 4H) 3.48-3.51 (m, 2H) 3.52-3.56 (m, 2H) 3.56- 3.61 (m, 4H) 3.67-3.75 (m, 2H) 3.86-3.96 (m, 2H) 4.15(s, 3H) 7.27 (d, J = 8.85 Hz, 2H) 7.64 (d, 1H) 7.77 (d, J = 8.85 Hz, 2H)7.90 (d, J = 7.93 Hz, 1H) 8.00 (s, 1H) 8.13-8.20 (m, 1H) 8.68 (s, 2H)

N-isopropyl- 4-(4-(4- methoxy-3-(2- oxo-2-(4-(1- (pyridin-2-yl)-1H-tetrazol-5- yl)piperazin- 1-yl)acetyl)- 1H- pyrrolo[2,3- c]pyridin-7-yl)phenyl) piperazine-1- carboxamide 679.74 2.24 (Method 4) ¹H NMR (500MHz, MeOD) δ ppm 1.19 (d, J = 6.71 Hz, 6H) 3.43- 3.51 (m, 6H) 3.52-3.57(m, 2H) 3.59-3.66 (m, 4H) 3.68-3.75 (m, 2H) 3.87-3.99 (m, 3H) 4.15 (s,3H) 7.27 (d, J = 8.85 Hz, 2H) 7.63 (dd, J = 7.32, 4.88 Hz, 1H) 7.77 (d,J = 8.85 Hz, 2H) 7.90 (d, J = 7.93 Hz, 1H) 8.00 (s, 1H) 8.12-8.21 (m,1H) 8.68 (s, 2H)

Preparation of1-(4-methoxy-7-(2-methoxythiazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

The general tin coupling procedure was applied in the preparation of1-(4-methoxy-7-(2-methoxythiazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(16 mg, 15%) from1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneusing 2-methoxy-5-(tributylstannyl)thiazole as a tin reagent. LCMS: m/e547.19 (M+H)⁺, ret time 1.28 min (method 8). ¹H NMR (500 MHz, DMSO-D6) δppm 3.22-3.31 (m, 2H) 3.44 (d, J=10.38 Hz, 4H) 3.67-3.76 (m, 2H)3.92-3.99 (m, 3H) 4.08 (s, 3H) 7.64 (dd, J=7.63, 4.88 Hz, 1H) 7.85 (d,J=8.24 Hz, 1H) 7.97-8.05 (m, 2H) 8.11-8.19 (m, 1H) 8.33 (d, J=3.36 Hz,1H) 8.64-8.70 (m, 1H) 12.66 (d, J=2.75 Hz, 1H).

Preparation of1-(7-(2-ethoxythiazol-5-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

The general tin coupling procedure was applied in the preparation of1-(7-(2-ethoxythiazol-5-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(30 mg, 27%) from1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneusing 2-ethoxy-5-(tributylstannyl)thiazole as a tin reagent. LCMS: m/e561.2 (M+H)⁺, ret time 1.39 min (method 8). ¹H NMR (500 MHz, MeOD) δ ppm1.52 (t, J=7.02 Hz, 3H) 3.46 (d, J=4.58 Hz, 2H) 3.52 (s, 2H) 3.69 (s,2H) 3.89 (d, J=5.19 Hz, 2H) 4.15 (s, 3H) 4.58-4.66 (m, 2H) 7.67 (dd,J=6.71, 4.88 Hz, 1H) 7.82-7.94 (m, 2H) 8.07 (s, 1H) 8.15-8.24 (m, 1H)8.64-8.73 (m, 2H).

Preparation of1-(4-methoxy-7-(2-methylthiazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

The general tin coupling procedure was applied in the preparation of1-(4-methoxy-7-(2-methylthiazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(22 mg, 21%) from1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneusing 2-methyl-5-(tributylstannyl)thiazole as a tin reagent. LCMS: m/e531.19 (M+H)⁺, ret time 1.12 min (method 8). ¹H NMR (500 MHz, MeOD) δppm 2.86 (s, 3H) 3.43-3.49 (m, 2H) 3.51-3.58 (m, 2H) 3.65-3.73 (m, 2H)3.87-3.94 (m, 2H) 4.13 (s, 3H) 7.62 (dd, J=7.48, 5.04 Hz, 1H) 7.89 (d,J=7.94 Hz, 1H) 8.10 (s, 1H) 8.12-8.19 (m, 1H) 8.25 (s, 1H) 8.52 (s, 1H)8.65-8.70 (m, 1H).

Preparation of1-(7-(2-ethylthiazol-5-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

The general tin coupling procedure was applied in the preparation of1-(7-(2-ethylthiazol-5-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(25 mg, 24%) from1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dioneusing 2-ethyl-5-(tributylstannyl)thiazole as a tin reagent. LCMS: m/e543.23 (M+H)⁺, ret time 1.43 min (method 8). ¹H NMR (500 MHz, MeOD) δppm 1.51 (t, J=7.48 Hz, 3H) 3.22 (q, J=7.63 Hz, 2H) 3.44-3.50 (m, 2H)3.51-3.57 (m, 2H) 3.66-3.73 (m, 2H) 3.87-3.93 (m, 2H) 4.15 (s, 3H) 7.62(dd, J=7.63, 4.88 Hz, 1H) 7.90 (d, J=8.24 Hz, 1H) 8.12 (s, 1H) 8.14-8.19(m, 1H) 8.30 (s, 1H) 8.59 (s, 1H) 8.68 (d, J=4.88 Hz, 1H).

A suspension of1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(100 mg, 0.195 mmol), pyrimidin-4-amine (55.7 mg, 0.586 mmol),Tris(dibenzylideneacetone)dipalladium(0) (8.94 mg, 9.76 μmol),4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (11.29 mg, 0.020 mmol)and Cesium carbonate (127 mg, 0.390 mmol) in Dioxane (2 mL) was heatedat 115° C. for 4 hours. After cooling to rt, the mixture was dilutedwith MeOH and filtered. The filtrate was concentrated and purified byprep. HPLC to give1-(4-methoxy-7-(pyrimidin-4-ylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(4.1 mg, 7.79 μmol, 3.99% yield). LCMS: m/e 527.3 (M+H)⁺, ret time 1.02min. 1H NMR (500 MHz, MeOD) δ ppm 8.87 (s, 1H) 8.61 (d, J=3.66 Hz, 1H)8.49 (d, J=6.10 Hz, 1H) 8.42 (s, 1H) 8.03-8.10 (m, 1H) 7.83 (d, J=7.94Hz, 1H) 7.67 (s, 1H) 7.51-7.56 (m, 2H) 4.02 (s, 3H) 3.83-3.90 (m, 2H)3.62-3.67 (m, 2H) 3.43-3.56 (m, 4H).

Example Chemistry Section C

The following general methods apply to Example Chemistry Section C:

HPLC Methods

#1 Dynamex C18, 4.6×250 mm, 8 micrometer, Sol. A 0.05% TFA in water/ACN(90:10), Sol. B 0.05% TFA in water/ACN (10:90), grad. 0% B to 100% B;

#2 Phenomenex Gemini C18, 4.6×150 mm, 5 micrometer, Sol. A 10 mMammonium bicarb (pH 7.8) in water/ACN (95:5), Sol. B 10 mM ammoniumbicarb (pH 7.8) in water/ACN (10:90), grad. 10% B to 50% B;

#3 Waters Xterra C18, 4.6×150 mm, 3.5 micrometer, Sol. A 10 nM ammoniumacetate (pH 6.8) in water/ACN (95:5). Sol. B 10 nM ammonium acetate (pH6.8) in water/ACN (10:90), grad. 5% B to 100% B (13.15 min retention).

Preparation of1-((2R,6S)-2,6-dimethyl-4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)-2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione(Compound C-1)

(3R,5S)-3,5-dimethyl-1-(1-phenyl-1H-tetrazol-5-yl)piperazine wasprepared via method A in chemistry section 1 using(2R,6S)-2,6-dimethylpiperazine and 5-chloro-1-phenyl-1H-tetrazole.(3R,5S)-3,5-dimethyl-1-(1-phenyl-1H-tetrazol-5-yl)piperazine was coupledwith2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid using method B for the preparation of compound 3 in chemistrysection A to provide the desired product1-((2R,6S)-2,6-dimethyl-4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)-2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dionewith the following characteristics:

Purity and Retention Times Obtained Via Each HPLC Method:

Method 1) 98.6% purity, 15.8 min. retention time

Method 2) 98.8% purity, 12.85 min. retention time

Method 3) 99.1% purity, 13.15 min retention time

MS 516 (M+H)+, 514 (M−H)−

HRMS cal. 516.2020

found 516.2007

mp. 254-256 deg. C.

H1 NMR DMSO-d6: 1.19-1.24 (t, 6H, J=6.6 Hz), 2.99-3.05 (dd, 1H, J=3.9,12.6 Hz), 3.15-3.21 (dd, 1H, J=4.5, 12.6 Hz), 3.24-3.42 (m, 2H),3.87-3.90 (m, 1H), 4.58-4.61 (m, 1H), 7.62-7.71 (m, 5H), 8.11-8.12 (d,1H, J=0.9 Hz), 8.30-8.31 (m, 2H), 9.00-9.01 (d, 1H, J=1.2 Hz), 13.04 (s,1H).

Example Chemistry Section D

The following general methods apply to Example Chemistry Section D:

LC-MS Analytical Method:

Method 1

Gradient time: 4 min

Flow rate: 3 mL/min

Stop time Gradient time+1 minute

Starting conc: 10% B

Eluent A: H₂O with 10 mM NH₄OAc

Eluent B: ACN

Column: Phenomenex, Onyx Monolithic C18 50×4.6 mm

Method 2

Gradient time: 3 min

Flow rate: 1 mL/min

Stop time Gradient time+1 minute

Starting conc: 0% B

Eluent A: 5:95 ACN:Water with 10 mM NH₄OAc

Eluent B: 95:5 ACN:Water with 10 mM NH₄OAc

Column: Waters Xbridge 2.1×50 mm 5 um C18

Method 3

Gradient time: 7.5 min

Flow rate: 1.2 mL/min

Stop time Gradient time+1 minute

Starting conc: 10% B

Eluent A: Water with 10 mM NH₄OAc

Eluent B: ACN

Column: Agilent Zorbax SB-CN 4.6×75 mm 3.5 micron

2-Keto acid (1 eq.), piperazine (1-5 eq.),O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1-5 eq.) and Hunig's Base (1-5 eq.) were combined in DMF. Themixture was stirred at room temperature for 17 hours. The product waspurified by Waters or Dinox automated preparative HPLC System.

2-Keto acid (1 eq.), piperazine (1-5 eq.),(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU) (1-5 eq.) and Hunig's Base (1-5 eq.) werecombined in DMF. The mixture was stirred at room temperature for 17hours. The product was purified by Waters or Dinox automated preparativeHPLC System.

TABLE D-1 MS (M + H)⁺ Observ. Compd Method MS (M + H)⁺ And RetentionTime # Structure Used Calcd. and NMR D-1

B 472.19 472.16 Rf = 1.64 min. LCMS Method 2 D-2

B 573.09 573.09 Rf = 1.73 min. LCMS Method 2 D-3

B 461.21 461.22 Rf = 1.63 min. LCMS Method 2 1H NMR (600 MHz,DMSO-_(d6)) δ ppm 12.36 (s, 1 H), 9.22 (s, 1 H), 8.23 (s, 1 H), 8.11 (s,1 H), 7.89 (s, 1 H), 7.52 (d, J = 6.44 Hz, 1 H), 6.95 (s, 1 H), 4.00 (s,3 H), 3.65-3.85 (m, 2 H), 3.41- 3.57 (m, 2 H), 3.19-3.30 (m, 3 H),3.12-3.21 (m, 2 H), 2.96- 3.10 (m, 2 H), 2.26 (s, 3 H) D-4

B 446.15 446.11 Rf = 1.59 min. LCMS Method 2 D-5

B 547.05 547.09 Rf = 1.70 min. LCMS Method 2 D-6

B 435.17 435.180 Rf = 1.60 min. LCMS Method 2 D-7

B 574.22 574.32 Rf = 1.71 min. LCMS Method 2 D-8

B 519.21 519.21 Rf = 1.63 min. LCMS Method 2 D-9

B 592.26 592.27 Rf = 1.74 min. LCMS Method 2 D-10

B 608.22 608.25 Rf = 1.86 min. LCMS Method 2 D-11

B 594.21 594.287 Rf = 1.71 min. LCMS Method 2 D-12

B 558.26 558.24 Rf = 1.61 min. LCMS Method 2 D-13

B 574.25 574.25 Rf = 1.41 min. LCMS Method 2 D-14

B 544.19 544.21 Rf = 1.41 min. LCMS Method 2 D-15

B 580.19 580.23 Rf = 1.79 min. LCMS Method 2 D-16

B 580.24 580.24 Rf = 1.55 min. LCMS Method 2 D-17

B 492.21 492.22 Rf = 1.62 min. LCMS Method 2 D-18

B 552.2 552.22 Rf = 1.51 min. LCMS Method 2 D-19

B 558.18 558.24 Rf = 1.56 min. LCMS Method 2 D-20

B 488.09 488.09 Rf = 1.68 min. LCMS Method 2 1H NMR (600 MHz,DMSO-_(d6)) δ ppm 12.38 (s, 1 H), 9.23 (s, 1 H), 8.29 (d, J = 11.13 Hz,1 H), 7.97 (s, 1 H), 4.04 (s, 3 H), 3.74-3.94 (m, 2 H), 3.53-3.68 (m, 4H), 3.43- 3.52 (m, 2 H), 3.22-3.41 (m, 3 H) D-21

B 572.28 572.28 Rf = 1.62 min. LCMS Method 2 D-22

B 566.23 566.29 Rf = 1.62 min. LCMS Method 2 D-23

B 548.19 548.28 Rf = 1.80 min. LCMS Method 2 D-24

B 493.18 493.18 Rf = 1.71 min. LCMS Method 2 D-25

B 566.22 566.24 Rf = 1.83 min. LCMS Method 2 D-26

B 582.19 582.20 Rf = 1.95 min. LCMS Method 2 D-27

B 568.17 568.24 Rf = 1.83 min. LCMS Method 2 D-28

B 532.22 532.21 Rf = 1.70 min. LCMS Method 2 D-29

B 548.22 548.23 Rf = 1.50 min. LCMS Method 2 D-30

B 518.15 518.19 Rf = 1.82 min. LCMS Method 2 D-31

B 554.15 554.23 Rf = 1.89 min. LCMS Method 2 D-32

B 526.18 526.20 Rf = 1.60 min. LCMS Method 2 D-33

B 532.13 532.21 Rf = 1.64 min. LCMS Method 2 D-34

B 546.24 546.26 Rf = 1.70 min. LCMS Method 2 D-35

B 480.19 480.33 Rf = 1.82 min. LCMS Method 2 D-36

B 542.21 542.27 Rf = 1.69 min. LCMS Method 2 D-37

B 549.25 549.29 Rf = 1.36 min. LCMS Method 2 D-38

B 534.20 534.33 Rf = 1.49 min. LCMS Method 2 D-39

B 545.18 545.26 Rf = 1.66 min. LCMS Method 2 D-40

B 549.20 549.33 Rf = 1.71 min. LCMS Method 2 D-41

B 563.22 563.28 Rf = 1.75 min. LCMS Method 2 D-42

B 577.23 577.31 Rf = 1.79 min. LCMS Method 2 D-43

B 591.25 591.32 Rf = 1.86 min. LCMS Method 2 D-44

B 605.27 605.40 Rf = 1.90 min. LCMS Method 2 D-45

B 502.18 502.24 Rf = 1.60 min. LCMS Method 2 D-46

B 516.19 516.27 Rf = 1.64 min. LCMS Method 2 D-47

B 497.17 497.24 Rf = 1.89 min. LCMS Method 2 D-48

B 564.19 564.34 Rf = 1.76 min. LCMS Method 2 D-49

B 506.23 506.18 Rf = 4.04 min. LCMS Method 2 D-50

B 568.24 568.23 Rf = 4.00 min. LCMS Method 3 D-51

B 575.29 575.25 Rf = 4.06 min. LCMS Method 3 D-52

B 560.24 560.20 Rf = 3.06 min. LCMS Method 3 D-53

B 571.22 571.18 Rf = 3.79 min. LCMS Method 3

Example Chemistry Section E Preparation of1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione

Part A: To a solution of 2-aminopyridine (9.41 g, 100 mmol) in methylenechloride (200 mL) at 25° C. was added thiocarbonyl diimidazole (18.75 g,100 mmol), and the resulting mixture was stirred at 25° C. for 20 h. Tothe reaction mixture then was added tert-butyl piperazine-1-carboxylate(18.60 g, 100 mmol), and the resulting mixture was stirred at 25° C. foranother 24 h. The mixture was diluted with diethyl ether, washed withwater (×3) and brine, dried over anhyd. sodium sulfate, filtered, andconcentrated. Column chromatography on silica gel (elution: 0-20%diethyl ether/methylene chloride) to afford tert-butyl4-(pyridin-2-ylcarbamothioyl)piperazine-1-carboxylate (13.60 g) as acolorless solid, following crystallization from a mixture of1-chlorobutane/hexane; ¹H NMR (300 MHz, CDCl₃) δ 7.97 (m, 1H), 7.64 (m,2H), 6.88 (m, 1H), 4.00 (m, 4H), 3.51 (m, 4H), 1.44 (s, 9H).

When commercially available the isothiocyanates were allowed to reactdirectly with tert-butyl piperazine-1-carboxylate in methylene chlorideat 25° C. The desired thiourea then was isolated as described above.

Part B: A mixture of tert-butyl4-(pyridin-2-ylcarbamothioyl)piperazine-1-carboxylate (15.30 g, 47.5mmol), potassium carbonate (13.10 g, 95.0 mmol), iodomethane (3.00 mL,47.5 mmol), and DMSO (200 mL) was stirred at 25° C. for 24 h. Thereaction mixture was diluted with ethyl acetate, washed with water (×4)and brine, dried over anhyd. sodium sulfate, filtered, and concentratedto provide tert-butyl4-(methylthio(pyridin-2-ylimino)methyl)piperazine-1-carboxylate (12.00g) as a waxy solid; ¹H NMR (300 MHz, CDCl₃) δ 8.25 (m, 1H), 7.63 (m,1H), 6.88 (m, 2H), 3.70 (m, 4H), 3.52 (m, 4H), 2.04 (s, 3H), 1.44 (s,9H).

Part C: To a solution of tert-butyl4-(methylthio(pyridin-2-ylimino)methyl)piperazine-1-carboxylate (12.00g, 36.0 mmol) in DMF (200 mL) at 25° C. was added sodium azide (11.60 g,178 mmol), followed by mercury(II)chloride (10.90 g, 40.0 mmol), and theresulting mixture was stirred at 25° C. for 19 d. The mixture then wasfiltered, and the solids were washed with DMF. The combined filtrate wasconcentrated under vacuum, and the residue was diluted with ethylacetate. The resulting mixture was filtered again. The filtrate waswashed with water (×3) and brine, dried over anhyd. sodium sulfate,filtered, and concentrated. Column chromatography on silica gel(elution: 0-20% diethyl ether/methylene chloride) to afford tert-butyl4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (10.10 g)as an off-white solid, following crystallization from a mixture of1-chlorobutane/hexane; Mass Spec.: m/e: 332.11 (M+H)⁺ [calc'd: 332.17];¹HNMR (300 MHz, CDCl₃) δ 8.57 (m, 1H), 7.94 (m, 1H), 7.79 (d, 1H, J=8Hz), 7.40 (m, 1H), 3.52 (m, 4H), 3.34 (m, 4H), 1.43 (s, 9H).

Part C′: When the procedures described above were employed utilizing2-amino-6-fluoropyridine as the commercial starting material theisolated crude product of part C was 3.90 g of a mixture of tert-butyl4-(1-(6-fluoropyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylateand tert-butyl4-(1-(6-azidopyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate.This crude product was dissolved in a mixture of 120 mL of methanol and20 mL of water. To this solution at 25° C. was added in portions 1.60 gof sodium borohydride, and the mixture was stirred at 25° C. for 4 h.The reaction mixture then was concentrated under vacuum, and the residuewas diluted with water and ethyl acetate. The phases were separated, andthe organic phase was washed with water (×2) and brine, dried overanhydrous sodium sulfate, filtered, and concentrated. Columnchromatography on silica gel (elution: 0-100% diethyl ether/methylenechloride) afforded tert-butyl4-(1-(6-fluoropyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate(3.26 g) [Mass Spec.: m/e: 350.32 (M+H)⁺ [calc'd: 350.17]; ¹H NMR (300MHz, CDCl₃) δ 8.05 (m, 1H), 7.78 (m, 1H), 7.05 (m, 1H), 3.60 (m, 4H),3.40 (m, 4H), 1.46 (s, 9H)] and tert-butyl4-(1-(6-aminopyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate(0.28 g) [Mass Spec.: m/e: 347.37 (M+H)⁺ [calc'd: 347.19]; ¹H NMR (300MHz, DMSO-D₆) δ 7.64 (t, 1H, J=8 Hz), 6.79 (d, 1H, J=8 Hz), 6.60 (d, 1H,J=8 Hz), 6.55 (br s, 2H), 3.40 (m, 4H), 3.24 (m, 4H), 1.41 (s, 9H)].

Part C″: To a solution of tert-butyl4-(1-(6-fluoropyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate(0.349 g, 1.00 mmol) in 20 mL of tetrahydrofuran at 25° C. was added asolution of lithium hydroxide monohydrate (0.084 g, 2.00 mmol) in 5 mLof water, and the resulting mixture was stirred at 25° C. for 11 days.The reaction mixture was diluted with water, the pH of the solution wasadjusted to ˜pH 6 employing aqueous sodium bisulfate solution, and themixture was extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. Column chromatography on silica gel (elution: 0-50%diethyl ether/methylene chloride) to afford tert-butyl4-(1-(6-hydroxypyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate(0.090 g); Mass Spec.: m/e: 348.24 (M+H)⁺ [calc'd: 348.18]; ¹H NMR (300MHz, CDCl₃) δ 7.84 (m, 1H), 7.21 (m, 1H), 6.89 (m, 1H), 3.52 (m, 4H),3.32 (m, 4H), 1.45 (s, 9H).

The following tetrazole intermediates were prepared from the indicatedcommercial starting materials employing the procedures described above.

Commercial MS (M + H)⁺ Starting Observ. (Calc'd) Structure material andNMR

332.17 (calc'd: 332.17) ¹H NMR (300 MHz, CDCl₃) δ8.92 (d, 1 H, J = 2.2Hz), 8.75 (d, 1 H, J = 4.7 Hz), 7.96 (m, 1 H), 7.52 (d of d, 1 H, J =8.0, 4.7 Hz), 3.49 (m, 4 H), 3.20 (m, 4 H), 1.42 (s, 9 H).

338.05 (calc'd: 338.13) ¹H NMR (300 MHz, CDCl₃) δ7.71 (d, 1 H, J = 3.5Hz), 7.38 (d, 1 H, J = 3.5 Hz), 3.57 (m, 4 H), 3.48 (m, 4 H), 1.44 (s, 9H).

322.17 (calc'd: 322.15) ¹H NMR (300 MHz, CDCl₃) δ7.77 (m, 1 H), 7.38 (m,1 H), 3.52 (m, 4 H), 3.40 (m, 4 H), 1.43 (s, 9 H).

337.23 (calc'd: 337.22) ¹H NMR (300 MHz, CDCl₃) δ3.99 (m, 1 H), 3.59 (m,4 H), 3.17 (m, 4 H), 2.01-1.93 (m, 6 H), 1.75 (m, 1 H), 1.46 (s, 9 H),1.42-1.31 (m,3 H).

¹H NMR (300 MHz, CDCl₃) δ7.41 (t, 1 H, J = 8.0 Hz), 7.16- 7.10 (m, 2 H),7.00 (d of d, 1 H, J = 8.0, 2.2 Hz), 3.83 (s, 3 H), 3.46 (m, 4 H), 3.19(m, 4 H), 1.42 (s, 9 H).

¹H NMR (300 MHz, CDCl₃) δ7.45 (d, 2 H, J = 9.2 Hz), 7.01 (d, 2 H, J =9.2 Hz), 3.85 (s, 3 H), 3.43 (m, 4 H), 3.17 (m, 4 H), 1.41 (s, 9 H).

356.17 (calc'd: 356.17) ¹H NMR (300 MHz, CDCl₃) δ7.97 (m, 1 H), 7.92 (m,1 H), 7.78 (m, 1 H), 7.69 (t, 1 H, J = 7.8 Hz), 3.50 (m, 4 H), 3.20 (m,4 H), 1.43 (s, 9 H).

356.19 (calc'd: 356.17) ¹H NMR (300 MHz, CDCl₃) δ7.83 (m, 4 H), 3.50 (m,4 H), 3.20 (m, 4 H), 1.42 (s, 9 H).

333.18 (calc'd: 333.18) ¹H NMR (300 MHz, CDCl₃) δ9.28 (d, 1 H, J = 5Hz), 8.11 (d, 1 H, J = 9 Hz), 7.76 (d of d, 1 H, J = 9, 5 Hz), 3.61 (m,4 H), 3.47 (m, 4 H), 1.46 (s, 9 H).

Part D: To a solution of tert-butyl4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (0.166 g,0.50 mmol) in 1,4-dioxane (10 mL) at 25° C. was added 4.00 N HCl in1,4-dioxane (10 mL), and the mixture was stirred at 25° C. for 16 h. Themixture then was concentrated under vacuum. The resulting solids weredissolved in DMF (10 mL). To this solution was added sequentially2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.137 g, 0.50 mmol), N-methylmorpholine (0.165 mL, 1.50 mmol), andTBTU (0.176 g, 0.55 mmol), and the mixture was stirred at 25° C. for 24h. The reaction mixture was filtered, and the filtrate was concentratedunder vacuum. The residue was dissolved in hot methanol, and thesolution then was allowed to cool slowly to room temperature. Theprecipitate was recovered by filtration, washed with methanol, and driedunder vacuum to provide1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(0.076 g) as an off-white solid; HRMS: 489.1662 (M+H)⁺ [calc'd:489.1660]; ¹H NMR (500 MHz, DMSO-D₆) δ 13.08 (br s, 1H), 9.02 (s, 1H),8.67 (m, 1H), 8.39 (s, 1H), 8.16 (t, 1H, J=7.8 Hz), 8.13 (s, 1H), 7.85(d, 1H, J=7.8 Hz), 7.64 (m, 1H), 3.74 (m 2H), 3.50 (m, 2H), 3.44 (m,2H), 3.26 (m, 2H).

The following compounds were prepared employing the procedures describedabove.

MS (M + H)⁺ Compd Observ. (Calc'd) # Structure and NMR E-2

HRMS: 515.2036 (calc'd. 515.2016) ¹H NMR (500 MHz, DMSO-D₆) δ12.41 (brs, 1 H), 9.24 (s, 1 H), 8.68 (m, 1 H), 8.25 (s, 1 H), 8.16 (d of d, 1 H,J = 7.8, 1.8 Hz), 7.89 (s, 1 H), 7.86 (d, 1 H, J = 7.8 Hz), 7.65 (d ofd, 1 H, J = 7.8, 5.0 Hz), 3.99 (s, 3 H), 3.72 (m, 2 H), 3.46 (m, 2 H),3.43 (m, 2 H), 3.27 (m, 2 H), 2.49 (s, 3 H). E-3

HRMS: 489.1662 (calc'd. 489.1660) ¹H NMR (500 MHz, DMSO-D₆) δ13.07 (brs, 1 H), 9.01 (s, 1 H), 8.92 (d, 1 H, J = 2.4 Hz), 8.78 (d of d, 1 H, J= 4.8, 1.8 Hz), 8.37 (s, 1 H), 8.31 (d, 1 H, J = 1.8 Hz), 8.19 (m, 1 H),8.12 (d, 1 H, J = 1.8 Hz), 7.69 (d of d, 1 H, J = 8.0, 4.8 Hz), 3.72 (m,2 H), 3.48 (m, 2 H), 3.35 (m, 2 H), 3.18 (m,2 H). E-4

HRMS: 495.1214 (calc'd. 495.1224) ¹H NMR (500 MHz, DMSO-D₆) δ13.06 (brs, 1 H), 9.02 (s, 1 H), 8.40 (s, 1 H), 8.31 (s, 1 H), 8.12 (s, 1 H),7.97 (d, 1 H, J = 3.4 Hz), 7.90 (d, 1 H, J = 3.4 Hz), 3.79 (m, 2 H),3.59 (m, 2 H), 3.56 (m, 2 H), 3.42 (m, 2 H). E-5

HRMS: 521.1579 (calc'd. 521.1580) ¹H NMR (500 MHz, DMSO-D₆) δ12.39 (brs, 1 H), 9.24 (s, 1 H), 8.27 (s, 1 H), 7.97 (d, 1 H, J = 3.4 Hz), 7.90(m, 2 H), 4.00 (s, 3 H), 3.77 (m, 2 H), 3.58 (m, 2 H), 3.52 (m, 2 H),3.43 (m, 2 H), 2.50 (s, 3 H). E-6

HRMS: 479.1431 (calc'd. 479.1453) ¹H NMR (500 MHz, DMSO-D₆) δ13.08 (brs, 1 H), 9.02 (s, 1 H), 8.44 (s, 1 H), 8.41 (s, 1 H), 8.33 (s, 1 H),8.13 (s, 1 H), 7.60 (s, 1 H), 3.78 (m, 2 H), 3.55 (m, 4 H), 3.36 (m, 2H). E-7

HRMS: 505.1795 (calc'd. 505.1809) ¹H NMR (500 MHz, DMSO-D₆) δ12.41 (brs, 1 H), 9.24 (s, 1 H), 8.45 (s, 1 H), 8.27 (s, 1 H), 7.89 (s, 1 H),7.61 (s, 1 H), 3.99 (s, 3 H), 3.76 (m, 2 H), 3.52 (m, 4 H), 3.37 (m, 2H), 2.50 (s, 3 H). E-8

HRMS: 494.2160 (calc'd. 494.2177) ¹H NMR (500 MHz, DMSO-D₆) δ13.10 (brs, 1 H), 9.02 (s, 1 H), 8.41 (s, 1 H), 8.33 (d, 1 H), J = 2.2 Hz), 8.12(s, 1 H), 4.22 (m, 1 H), 3.83 (m, 2 H), 3.59 (m, 2 H), 3.35 (m, 2 H),3.20 (m, 2 H), 2.00 (m, 2 H), 1.79 (m, 4 H), 1.67 (m, 1 H), 1.45 (m, 2H), 1.26 (m, 1 H), E-9

HRMS: 518.1797 (calc'd. 518.1813) ¹H NMR (500 MHz, DMSO-D₆) δ13.06 (brs, 1 H), 9.01 (s, 1 H), 8.36 (s, 1 H), 8.31 (d, 1 H), J = 2.2 Hz), 8.12(s, 1 H), 7.52 (t, 1 H), J = 8.0 Hz), 7.24 (m, 2 H), 7.15 (m, 1 H), 3.82(s, 3 H), 3.71 (m, 2 H), 3.48 (m, 2 H), 3.35 (m, 2 H), 3.18 (m, 2H).E-10

HRMS: 518.1808 (calc'd. 518.1813) ¹H NMR (500 MHZ, DMSO-D₆) δ13.06 (brs, 1 H), 9.01 (d, 1 H, J = 1.2 Hz), 8.35 (s, 1 H), 8.31 (d, 1 H), J =2.2 Hz), 8.12 (d, 1 H, J = 1.2 Hz), 7.58 (d, 2 H), J = 8.8 Hz), 7.14 (d,2 H, J = 8.8 Hz), 3.82 (s, 3 H), 3.70 (m, 2 H), 3.46 (m, 2 H), 3.34 (m,2 H), 3.15 (m, 2 H). E-11

HRMS: 511.1495 (M − H)⁻ (calc'd. 511.1503) ¹H NMR (500 MHz, DMSO-D₆)δ13.07 (br s, 1 H), 9.01 (s, 1 H), 8.38 (s, 1 H), 8.31 (d, 1 H, J = 2.2Hz), 8.25 (s, 1 H), 8.12 (s, 1 H), 8.06 (m, 2 H), 7.83 (t, 1 H, J = 8.0Hz), 3.72 (m, 2 H), 3.48 (m, 2 H), 3.35 (m, 2 H), 3.17 (m, 2 H). E-12

HRMS: 511.14883 (M − H)⁻ (calc'd. 511.1503) ¹H NMR (500 MHz, DMSO-D₆)δ13.07 (br s, 1 H), 9.01 (s, 1 H), 8.37 (s, 1 H), 8.31 (d, 1 H. J = 2.2Hz), 8.12 (m, 3 H), 7.94 (d, 2 H, J = 8.9 Hz), 3.74 (m, 2 H), 3.50 (m, 2H), 3.35 (m, 2 H), 3.16 (m, 2 H). E-12a

HRMS: 533.1923 (calc'd. 533.1922) ¹H NMR (500 MHz, DMSO-D₆) δ12.40 (brs, 1 H), 9.24 (s 1 H), 8.34 (m, 1 H), 8.26 (s, 1 H), 7.89 (s, 1 H), 7.83(d, 1 H, J = 8 Hz), 7.46 (d, 1 H, J = 8 Hz), 3.99 (s, 3 H), 3.74 (m, 2H), 3.47 (m, 4 H), 3.29 (m, 2 H), 2.49 (s, 3 H). E-12b

HRMS: 530.2122 (calc'd. 530.2125) ¹H NMR (500 MHz, DMSO-D₆) δ12.39 (brs, 1 H), 9.24 (s, 1 H), 8.24 (s, 1 H), 7.89 (s, 1 H), 7.63 (t, 1 H, J =8 Hz), 6.80 (d, 1 H, J = 8 Hz), 6.58 (d, 1 H, J = 8 Hz), 6.55 (br s, 2H), 3.98 (s, 3 H), 3.73 (m, 2 H), 3.47 (m, 2 H), 3.43 (m, 2 H), 3.30 (m,2 H), 2.49 (s, 3 H). E-12c

HRMS: 531.1969 (calc'd. 531.1965) ¹H NMR (500 MHz, DMSO-D₆) δ12.40 (brs, 1 H), 11.58 (br s, 1 H), 9.24 (s, 1 H), 8.25 (s, 1 H), 7.94 (t, 1 H,J = 8 Hz), 7.90 (s, 1 H), 7.25 (d, 1 H, J = 8 Hz), 6.86 (d, 1 H, J = 8Hz), 3.99 (s, 3 H), 3.73 (m, 2 H), 3.47 (m, 2 H), 3.43 (m, 2 H), 3.28(m, 2 H), 2.50 (s, 3 H). E-12d

HRMS: 516.1964 (calc'd. 516.1969) ¹H NMR (500 MHz, DMSO-D₆) δ12.40 (brs, 1 H), 9.45 (d, 1 H, J = 4.9 Hz), 9.24 (s, 1 H), 8.26 (s, 1 H), 8.23(d, 1 H, J = 8.5 Hz), 8.09 (d of d, 1 H, J = 8.5, 4.9 Hz), 7.90 (s, 1H), 3.99 (s, 3 H), 3.74 (m, 2 H), 3.47 (m, 4 H), 3.30 (m, 2 H), 2.51 (s,3 H).

Preparation of1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperidin-1-yl)ethane-1,2-dione(Compound E-13)

Part A: To a solution of N-Boc-isonipecotic acid (4.85 g, 21.2 mmol) intetrahydrofuran (80 mL) at 25° C. was added carbonyl diimidazole (3.80g, 23.3 mmol), and the reaction mixture was stirred for 1.00 h at 25° C.To the resulting mixture was added aniline (2.10 mL, 23.3 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) (3.20 mL, 21.2 mmol), and thesolution was stirred at 25° C. for another 90 h. The reaction mixturewas diluted with water, 1.00 N hydrochloric acid (80 mL), and ethylacetate. The phases were separated, and the organic phase was washedwith water (×2) and brine, dried over anhyd. sodium sulfate, filtered,and concentrated. Column chromatography on silica gel (elution: 0-20%diethyl ether/methylene chloride) furnished tert-butyl4-(phenylcarbamoyl)-piperidine-1-carboxylate (4.25 g) as a white solid;¹H NMR (300 MHz, CDCl₃) δ 7.48 (d, 2H, J=8.0 Hz), 7.29 (t, 2H, J=8.0Hz), 7.20 (br s, 1H), 7.08 (t, 1H, J=8.0 Hz), 4.16 (m, 2H), 2.75 (m,2H), 2.35 (m, 1H), 1.89-1.61 (m, 4H), 1.43 (s, 9H).

Part B: To a solution of tert-butyl4-(phenylcarbamoyl)piperidine-1-carboxylate (4.24 g, 13.9 mmol) anddiisopropylazodicarboxylate (5.40 mL, 27.9 mmol) in tetrahydrofuran (100mL) at 25° C. was added triphenylphosphine (7.31 g, 27.9 mmol). Theresulting reaction mixture showed a slight exotherm, and the solutionthen was stirred at ambient temperature for ˜0.25 h until the reactionmixture had returned to 25° C. To the resulting mixture was addedazidotrimethylsilane (3.65 mL, 27.9 mmol). A precipitate formed withinminutes, and the mixture then was stirred at 25° C. for 7 days. Thereaction mixture was concentrated under vacuum to afford the crudeproduct. Column chromatography on silica gel (elution: 10-50% ethylacetate/hexane) afforded tert-butyl4-(1-phenyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (2.58 g) as awhite solid, following crystallization from a mixture of1-chlorobutane/hexane; ¹H NMR (300 MHz, CDCl₃) δ 7.58 (m, 3H), 7.38 (m,2H), 4.12 (m, 2H), 2.98 (m, 1H), 2.76 (m, 2H), 1.96-1.74 (m, 4H), 1.42(s, 9H).

Part C: To a solution of tert-butyl4-(1-phenyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (0.165 g, 0.50mmol) in 1,4-dioxane (10 mL) at 25° C. was added 4.00 N HCl in1,4-dioxane (10 mL), and the mixture was stirred at 25° C. for 16 h. Themixture then was concentrated under vacuum. The resulting solids weredissolved in DMF (10 mL). To this solution was added sequentially2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.137 g, 0.50 mmol), N-methylmorpholine (0.165 mL, 1.50 mmol), andTBTU (0.176 g, 0.55 mmol), and the mixture was stirred at 25° C. for 24h. The reaction mixture was filtered, and the filtrate was concentratedunder vacuum. The residue was dissolved in hot methanol, and thesolution then was allowed to cool slowly to room temperature. Theprecipitate was recovered by filtration, washed with methanol, and driedunder vacuum to provide1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperidin-1-yl)ethane-1,2-dione(0.142 g) as an off-white solid; mp: 257-258° C.; HRMS: 487.1740 (M+H)⁺[calc'd: 487.1755]; ¹H NMR (500 MHz, DMSO-D₆) δ 13.06 (br s, 1H), 9.02(s, 1H), 8.32 (d, 1H, J=1.8 Hz), 8.30 (s, 1H), 8.12 (s, 1H), 7.58 (s,5H), 4.37 (m, 1H), 3.67 (m, 1H), 3.32 (m, 1H), 3.25 (m, 1H), 3.03 (m,1H), 2.01 (m, 1H), 1.88 (m, 1H), 1.83-1.70 (m, 2H).

Preparation of1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound E-14) and1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound E-15)

Part A: To a solution of ethyl 3,3-diethoxypropionate (90% tech.) (5.28g, 25 mmol) in 50 mL of THF was added 1.00 N sodium hydroxide in water(25.00 mL, 25 mmol), and the resulting mixture was stirred at 25° C. for18 h. The mixture then was concentrated under vacuum to afford aresidual white solid. This solid was dissolved in 50 mL of DMF. To thesolution was added EDCI (5.75 g, 30.0 mmol), 1-hydroxybenzotriazole(4.56 g, 33.8 mmol), and benzyl piperazine-1-carboxylate (5.51 g, 25.0mmol), and the resulting mixture was stirred at 25° C. for 24 h. Thereaction mixture was concentrated under vacuum, and the residue wasdiluted with water. The aqueous mixture was extracted with ethylacetate, and the combined extracts were washed aqueous sodiumbicarbonate solution and brine, dried over anhydrous sodium sulfate,filtered, and concentrated. Column chromatography on silica gel(elution: 10-40% ethyl acetate/chloroform) furnished 8.00 g (88%) ofbenzyl 4-(3,3-diethoxypropanoyl)piperazine-1-carboxylate as an oil; ¹HNMR (500 MHz, CDCl₃) δ 57.34 (m, 5H), 5.14 (s, 2H), 4.90 (t, 1H, J=5.5Hz), 3.73-3.46 (m, 12H), 2.68 (d 2H, J=5.5 Hz), 1.19 (t, 6H, J=7.0 Hz).

Part B: To a solution of benzyl4-(3,3-diethoxypropanoyl)piperazine-1-carboxylate (3.39 g, 9.30 mmol) in30 mL of chloroform at 0° C. was added a solution of 10.0 mL of waterand 10.0 mL of trifluoroacetic acid, and the resulting biphasic mixturewas stirred at 25° C. for 20 h. The mixture then was diluted withadditional chloroform, washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated. The residue then wasdissolved in 50 mL of ethanol. To this solution was added2-hydrazinopyridine (1.015 g, 9.30 mmol) and methanesulfonic acid (0.060mL, 0.930 mmol), and the resulting mixture was stirred at 25° C. for 18h. Pyridine (1.00 mL) was added, and then the reaction mixture wasconcentrated under vacuum. The residue was dissolved in 50 mL ofpyridine. To this solution was added phosphorous oxychloride (1.73 mL,18.6 mmol), and the mixture was stirred at 25° C. for 20 h. The mixturewas concentrated under vacuum. The residue was diluted with water andethyl acetate, and the phases were separated. The organic phase waswashed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated. Column chromatography on silica gel(elution: 10-50% ethyl acetate/methylene chloride) afforded 0.38 g(11.2%) of benzyl4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine-1-carboxylate as an oil;Mass Spec.: m/e: 364.20 (M+H)⁺ [calc'd: 364.18]; ¹H NMR (500 MHz,DMSO-D₆) δ 8.53 (d, 1H, J=5.0 Hz), 7.97 (t, 1H, J=8.0 Hz), 7.73 (d, 1H,J=8.0 Hz), 7.58 (s, 1H), 7.40-7.30 (m, 6H), 6.04 (s, 1H), 5.10 (s, 2H),3.49 (m, 4H), 2.94 (m, 4H).

Part C: A mixture of benzyl4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine-1-carboxylate (0.34 g,0.936 mmol) and 10% palladium/carbon (0.34 g) in 20.0 mL of methanol wasstirred at 25° C. under hydrogen gas (1.00 atm) for 5 h. The resultingmixture was filtered, and the solids were washed with additionalmethanol. The combined filtrate was concentrated under vacuum. Theresidue was dissolved in 20 mL of 1,4-dioxane. To this solution wasadded hydrogen chloride (4.00 N in 1,4-dioxane) (0.468 mL, 1.871 mmol),and the resulting suspension was concentrated under vacuum to afford awhite powder. This hydrochloride salt of the piperazine then wasemployed in procedures analogous to Part C in the preparation ofcompound E-13 to provide1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound E-14) and1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(Compound E-15).

Compound E-14: HRMS: m/e: 487.1749 (M+H)⁺ [calc'd: 487.1755]; ¹H NMR(500 MHz, DMSO-D₆) δ 13.02 (br s, 1H), 9.02 (s, 1H), 8.54 (m, 1H), 8.37(s, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.97 (m, 1H), 7.74 (m, 1H), 7.59(s, 1H), 7.38 (m, 1H), 6.08 (s, 1H), 3.74 (m, 2H), 3.50 (m, 2H), 3.11(m, 2H), 2.99 (m, 2H).

Compound E-15: HRMS: m/e: 513.2102 (M+H)⁺ [calc'd: 513.2111]; ¹HNMR (500MHz, DMSO-D₆) δ 12.40 (br s, 1H), 9.25 (s, 1H), 8.54 (m, 1H), 8.24 (s,1H), 7.98 (t, 1H, J=7.8 Hz), 7.90 (s, 1H), 7.75 (d, 1H, J=7.8 Hz), 7.60(s, 1H), 7.39 (m, 1H), 6.10 (s, 1H), 4.01 (s, 3H), 3.71 (m, 2H), 3.45(m, 2H), 3.10 (m, 2H), 2.99 (m, 2H), 2.50 (s, 3H).

Preparation of1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)piperazin-1-yl)ethane-1,2-dione(Compound E-16) and1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)piperazin-1-yl)ethane-1,2-dione(Compound E-17)

Part A: To a mixture of tert-butyl piperazine-1-carboxylate (1.863 g,10.00 mmol) and cesium carbonate (6.52 g, 20.00 mmol) in 50 mL of DMF at25° C. was added 2-(bromoacetyl)pyridine hydrobromide (2.81 g, 10.00mmol) in portions over five minutes. The reaction mixture then wasstirred at 25° C. for 3 h. The resulting mixture was diluted with waterand ethyl acetate. The phases were separated, and the organic phase waswashed with water (×3) and brine, dried over anhydrous sodium sulfate,filtered, and concentrated. Column chromatography on silica gel(elution: 10-50% ethyl acetate/chloroform) provided 1.61 g (53%) oftert-butyl 4-(2-oxo-2-(pyridin-2-yl)ethyl)piperazine-1-carboxylate as acrystalline solid; ¹H NMR (500 MHz, CDCl₃) δ 8.63 (d, 1H, J=4.5 Hz),8.05 (m, 1H), 7.85 (t, 1H, J=9 Hz), 7.49 (m, 1H), 4.30 (s, 2H), 3.62 (m,4H), 2.75 (m, 4H), 1.46 (s, 9H).

Part B: A solution of tert-butyl4-(2-oxo-2-(pyridin-2-yl)ethyl)piperazine-1-carboxylate (1.46 g, 4.78mmol) and N,N-dimethylformamide dimethyl acetal (10.00 mL, 75 mmol) washeated at reflux for 5 h. After cooling to room temperature the mixturewas concentrated under vacuum. The residue was dissolved in 20 mL ofethanol. To this solution was added anhydrous hydrazine (1.50 mL, 47.8mmol), and the mixture was heated at reflux for 2 h. After cooling toroom temperature the reaction mixture was concentrated under vacuum, andthe residue was dissolved in ethyl acetate. The solution then was washedwith aqueous sodium bicarbonate solution and brine, dried over anhydroussodium sulfate, filtered, and concentrated. Column chromatography onsilica gel (elution: 1-5% isopropanol/chloroform w/0.5% conc. ammonia)provided 0.600 g (38%) of tert-butyl4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)piperazine-1-carboxylate as an oil;Mass Spec.: m/e: 330.30 (M+H)⁺ [calc'd: 330.19]; ¹H NMR (300 MHz,DMSO-D₆) δ 13.19 (br s, 1H), 8.60 (m, 1H), 8.09 (m, 1H), 7.90 (m, 1H),7.53 (m, 1H), 7.31 (m, 1H), 3.50 (m, 4H), 2.82 (m, 4H), 1.43 (s, 9H).

Part C: The tert-butyl4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)piperazine-1-carboxylate then wasemployed in procedures analogous to Part C in the preparation ofcompound E-13 to provide1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)piperazin-1-yl)ethane-1,2-dione(Compound E-16) and1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridinyl-3-yl)-2-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)piperazin-1-yl)ethane-1,2-dione(Compound E-17).

Compound E-16: HRMS: m/e: 487.1747 (M+H)⁺ [calc'd: 487.1755]; ¹H NMR(500 MHz, DMSO-D₆) δ 13.07 (br s, 1H), 9.03 (s, 1H), 8.61 (m, 1H), 8.37(m, 1H), 8.33 (m, 1H), 8.13 (m, 2H), 7.96 (m, 1H), 7.56 (m, 1H), 7.32(m, 1H), 3.84 (m, 2H), 3.59 (m, 2H), 3.00 (m, 2H), 2.89 (m, 2H).

Compound E-17: HRMS: m/e: 513.2104 (M+H)⁺ [calc'd: 513.2111]; ¹HNMR (500MHz, DMSO-D₆) δ 12.40 (br s, 1H), 9.25 (s, 1H), 8.61 (m, 1H), 8.25 (m,1H), 7.91 (m, 3H), 7.57 (m, 1H), 7.31 (m, 1H), 4.04 (s, 3H), 3.81 (m,2H), 3.54 (m, 2H), 3.00 (m, 2H), 2.88 (m, 2H), 2.50 (s, 3H).

Example Chemistry Section F Preparation of the Library of AmidoPyrazoles

A mixture of3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid (42 mg, 0.8 mmol), an amine (3.36 mmol), TBTU (0.88 mmol) and DIPEA(38.4 mmol) was agitated at room temperature overnight. The crudereaction mixtures were purified using reverse phase prep HPLC.

LC Conditions Used to Analyze Final Compounds:

Column: Waters Xbridge 4.6×50 mm 5 um C18

Method: 10% B/90% A+modifier to 95% B/5% A+modifier

A=Water

B=ACN

Modifier=10 mM NH4OAc

Flow=2.5 mL/min

Gradient time: 4 min

Stop time: 5 min

Comp. # Structure LC/MS data Amine F-1

Rt: 2.13 min. Reported Mass: 613.360

F-2

Rt: 2.05 min. Reported Mass: 627.410

F-3

Rt: 2.10 min. Reported Mass: 600.330

F-4

Rt: 2.20 min. Reported Mass: 697.450

F-5

Rt: 2.12 min. Reported Mass: 641.390

F-6

Rt: 2.25 min. Reported Mass: 614.360

F-7

Rt: 2.08 min. Reported Mass: 712.490

F-8

Rt: 2.03 min. Reported Mass: 643.400

F-9

Rt: 2.40 min. Reported Mass: 572.320

F-10

Rt: 2.49 min. Reported Mass: 602.270

F-11

Rt: 2.18 min. Reported Mass: 614.360

F-12

Rt: 2.19 min. Reported Mass: 655.420

F-13

Rt: 2.02 min. Reported Mass: 641.440

F-14

Rt: 2.07 min. Reported Mass: 615.350

F-15

Rt: 2.21 min. Reported Mass: 657.430

F-16

Rt: 2.10 min. Reported Mass: 614.360

Example Chemistry Section G Preparation of Compound G-1a and G-2b

Step-1

Sodium hydride (0.12 g) was taken in dry DMF (5 ml) and a solution of3-amino-4-phenyl isoxazole (0.2 g in 2 ml of DMF) was added slowly at 0°C. The reaction mixture was stirred for 30 min at 0° C. and a solutionof bis-(2-chloroethylamine) hydrochloride (0.22 g) in DMF (1 mL) wasadded very slowly. The reaction mixture was allowed to stir over nightat room temperature. The reaction mixture was quenched with cold water(5 ml) and extracted with ethyl acetate (3×40 ml). Evaporation ofsolvent under reduced pressure gave crude product, which, was purifiedby column chromatography using MeOH/CHCl₃ (2:8) as eluent to affordG-1-In as pure solid product.

¹H NMR (400 MHz, CDCl₃): δ 3.02 (d, 4H), 3.50 (d, 4H), 7.27-7.80 (m,5H).

LCMS: 230.9 (M⁺+1).

Step-2

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.18 g), G-1-In (0.1 g), TBTU (0.15 g) and Hunig's base (0.15 ml)were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-1a asyellow solid.

¹H NMR (400 MHz, CDCl₃): δ 2.58 (s, 3H), 3.26 (bs, 2H), 3.36 (bs, 2H),3.63 (bs, 2H), 3.89 (bs, 2H), 4.06 (s, 3H), 7.53 (s, 3H), 7.77 (d, 3H,J=8 Hz), 8.21 (s, 1H), 9.13 (s, 1H), 11.04 (s, 1H).

¹³C NMR (400 MHz, CDCl₃): δ 14.04, 40.48, 45.1, 48.91, 49.26, 57.02,115.77, 121.39, 123.2, 124.14, 126.25, 127.79, 129.21, 129.55, 130.7,136.52, 141.13, 147.66, 149.71, 158.53, 166.37, 185.23.

LCMS: 514.1 (M⁺+1), 512.6 (M⁺−1).

HPLC: 97.6% (NH₄OAc/ACN; Column: C18 XDB, 250×4.6 mm).

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.18 g), G-1-In (0.1 g), TBTU (0.15 g) and Hunig's base (0.15 ml)were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-1b asyellow solid.

¹H NMR (400 MHz, CDCl₃): δ 3.27 (t, 2H, J=6 Hz), 3.35 (t, 2H, J=6 Hz),3.71 (t, 2H, J=6 Hz), 3.90 (t, 2H, J=6 Hz), 7.52 (t, 3H, J=4 Hz), 7.78(d, 2H, J=8 Hz), 7.94 (s, 1H), 8.16 (s, 1H), 8.39 (s, 1H), 8.77 (s, 1H),11.29 (s, 1H).

LCMS: 488.1 (M⁺+1).

HPLC: 96.6% (NH₄OAc/ACN; Column: C18 XDB, 250×4.6 mm).

Preparation of Compound G-2a, G-2b and G-2c Preparation of IntermediateG-2-In

Step-1

To 4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridine hydrochloride (50 g) taken in2 L 3-necked round bottom flask, 250 ml N-methyl-2-pyrrolidinone wasadded followed by 8 ml of water, and was heated to 90° C. for about 4hrs. The reaction mixture was cooled to room temperature, diluted withwater (1 L) and the whole mixture was kept in cold room for about onehour. The resulting solid was collected by filtration, washed with coldwater and dried in vacuum oven at 50° C. for 4 hrs to afford7-hydroxyl-4-methoxy-6-azaindole as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.70 (s, 3H), 6.32-6.33 (dd, 1H), 6.38 (s,1H), 7.25-7.26 (d, 1H, J=4 Hz), 10.5 (bs, 1H), 12.1 (bs, 1H).

Step-2

To the above compound 7-hydroxyl-4-methoxy-6-azaindole (33 g) taken insingle necked round bottom flask, phosphorusoxychloride (400 ml) wasadded and the mixture was heated to 100° C. for 18 hrs. Reaction mixturewas cooled to room temperature and concentrated to remove excessphosphorus oxychloride. Residue was slowly poured into ice andneutralized with solid sodium bicarbonate. The mixture was extractedwith Ethyl acetate (3×100 ml). The combined organic layer was dried overanhydrous sodium sulphate and concentrated to afford7-chloro-1-4-methoxy-6-azaindole as white solid.

¹H NMR (400 MHz, CDCl₃): δ 4.03 (s, 3H), 6.73-6.74 (dd, 1H), 7.36-7.37(t, 1H), 7.63 (s, 1H) 8.9 (bs, 1H).

LCMS: 182.7 (M⁺+1).

Step-3

A solution of 7-chloro-4-methoxy-6-azaindole (3 g) and aluminiumchloride (2.3 g) in 100 ml dichloromethane was added to a mixture ofmethylchlorooxalate (6 g) and aluminium chloride (3.7 g) in 50 ml ofdichloromethane. The whole mixture was stirred at room temperature for18 hrs under nitrogen atmosphere. Reaction mixture was quenched with 100ml of saturated aqueous ammonium acetate solution and extracted withethyl acetate (2×100 ml). The combined organic layers was washed withbrine solution, dried over anhydrous sodiumsulphate, filtered andconcentrated under reduced pressure. The resulting crude product wastreated with methanol and filtered to give pure ester as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.85-3.88 (s, 3H), 3.94 (s, 3H), 7.83 (s,1H), 8.45 (s, 1H), 13.3 (bs, 1H).

Step-4

Above ester (1 g) and K₂CO₃ (0.95 g) were combined in 6 ml ofmethanol/water (1:1) mixture and stirred at room temperature for overnight. The mixture was extracted with ethyl acetate to remove thenon-polar impurities. And the aqueous layer was neutralized with 1.5 NHCl to pH5. The reaction mixture was concentrated under reduced pressureto afford desired acid,2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acidwhich was used for the next step without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 3.91 (s, 3H), 7.79 (s, 1H), 8.35 (s, 1H),13.30 (bs, 1H).

LCMS: 254.9 (M⁺+1).

Step-5

To sodium hydride (2.1 g) taken in dry DMF (10 ml),5-chloro-1H-tetrazole (5 g) dissolved in dry DMF (20 ml) was added dropwise at 0° C. under nitrogen. Reaction mixture was allowed to stir at 0°C. for about 30 min and piperazine (2.8 g) in DMF (10 ml) was added dropwise at 0° C. for about 10 min. The whole mixture was heated to 80° C.for 18 hrs then cooled to room temperature and slowly poured into ice.The resulting solid was filtered, washed with water and dried to afford1-(1-phenyl-1H-tetrazol-5-yl)piperazine as a solid product.

¹H NMR (400 MHz, CDCl₃): δ 2.91-2.93 (m, 4H), 3.22-3.33 (m, 4H),7.49-7.63 (m, 5H).

Step-6

To 2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid(0.15 g) taken in dry DMF (3 ml), 1-(1-phenyl-1H-tetrazol-5-yl)pauperizing (0.1 g), TBTU (0.219 g) and Hunig's base (0.2 ml) wereadded. The reaction mixture was stirred at room temperature for overnight. The reaction was quenched with methanol (10 ml) and the volatileswere removed under reduced pressure. The resulting oil was diluted withethyl acetate (50 ml), washed with 10% NaHCO₃ (2×20 ml) and brine (20ml). The organic layer was dried over anhydrous Na₂SO₄ and afterconcentration under reduced pressure. The resulting crude was purifiedby column chromatography using MeOH/CHCl₃ (1:9) as eluent to affordG-2-In as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.31-3.34 (s, 3H), 3.39 (bs, 2H), 3.47 (bs,2H), 3.87-3.91 (s, 2H), 4.09 (s, 3H), 7.57 0-7.7 (s, 1H), 8.31-8.34 (d,1H), 13.3 (bs, 1H).

LCMS: 465.3 (M⁺+1).

Preparation of G-2a

Step-1

To sodium hydride (0.20 g) taken in dry THF (15 ml), N-methyl piperazine(0.93 ml) was added under nitrogen at 0° C. 2,3-Dibromopyrazine (2 g)taken in 15 ml dry THF was added to the above mixture at 0° C. Thereaction mixture was allowed to reflux for overnight and quenched withwater (5 ml). The organic layer was removed under vacuum. The resultingcrude mass was purified by column chromatography to afford2-bromo-5-(4-methylpiperazin-1-yl)pyrazine as pure product.

¹H NMR (400 MHz, CDCl₃): δ 2.39 (s, 3H), 2.57 (t, 4H, J=6 Hz), 3.62 (t,4H, J=6 Hz), 7.88 (s, 1H), 8.14 (s, 1H).

Step-2

To the compound 2-bromo-5-(4-methylpiperazin-1-yl)pyrazine (0.25 g)dissolved in dry DMF (5 ml), hexa-n-butyl di-tin (0.615 ml) was added.The reaction mixture was degasified under argon atmosphere for 3-5times. Tetrakis (triphenyl phosphine) palladium (0.128 g) was added tothe above mixture and further degasified under argon atmosphere for 3-5times. The reaction mixture was refluxed overnight, then cooled to roomtemperature, diluted with ethyl acetate and filtered through celite bed.The filtrate was concentrated and purified by column chromatography toafford compound 2-(4-methylpiperazin-1-yl)-5-(tributylstannyl)pyrazineas pale yellow color liquid.

¹H NMR (400 MHz, CDCl₃): δ 1.36 (s, 10H), 1.58 (s, 6H), 1.63 (s, 6H),1.69 (s, 6H), 2.39 (s, 3H), 3.95 (s, 4H), 4.07 (s, 4H), 8.18 (s, 1H),9.30 (s, 1H).

Step-3

To a stirred solution of intermediate2-(4-methylpiperazin-1-yl)-5-(tributylstannyl)pyrazine (0.25 g) andG-In-2 (0.38 g) taken in dry xylene (15 ml) under nitrogen atmosphere,copper (I) iodide (10 mg) was added. The reaction mixture was degasifiedusing nitrogen and to that mixture Pd(Ph)₄ (0.065 g) was added. Thereaction mixture was refluxed for 24 hours at 130° C. The reactionmixture was cooled to room temperature and concentrated under vacuum toremove the solvent. The resulting crude was purified by columnchromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-2a as whitesolid product.

¹H NMR (400 MHz, DMSO-d₆): δ 2.26 (s, 3H), 3.16 (s, 2H) 3.32 and 3.42(m, 7H), 3.67 (s, 7H), 3.97 (s, 3H), 7.57-7.64 (m, 3H), 7.69 (d, 2H, J=8Hz), 8.10 (s, 1H), 8.18 (d, 1H, J=4 Hz), 8.33 (s, 1H), 9.07 (s, 1H),12.45 (s, 1H).

LCMS: 609.2 (M⁺+1).

HPLC: 95.3% (NH₄OAc+0.1% TFA/ACN; Column: C18 XDB, 250×4.6 mm).

Preparation of G-2b

Step-1

To sodium hydride (0.20 g) taken in THF (15 ml), morpholine (0.735 ml)was added under nitrogen, at 0° C. The reaction mixture stirred forabout 15 minutes, then 2,3-dibromopyrazine (2 g) dissolved in dry THF(15 ml) was added. The reaction mixture was allowed to stir at refluxconditions for overnight. The reaction mixture was quenched with water(5 ml), and volatiles were removed under vacuum. The resulting crudemass was purified by column chromatography to afford pure4-(5-bromopyrazin-2-yl)morpholine.

¹H NMR (400 MHz, CDCl₃): δ 3.53 (t, 4H, J=6 Hz), 3.84 (t, 4H, J=6 Hz),7.88 (s, 1H), 8.16 (s, 1H).

Step-2

To compound 4-(5-bromopyrazin-2-yl)morpholine (0.25 g) taken in dry THF(5 ml) and cooled to −78° C., n-butyl lithium (0.4 ml, 1M solution inHexane) was added stirred for 2 hrs at −78° C. To the above reactionmixture tri-n-butyl tin chloride (1.1 mmol) was added drop wise at −78°C. Reaction mixture was stirred at −78° C. for one hour, quenched withsaturated ammonium chloride solution and extracted with ethyl acetate(3×15 ml). The organic layer was washed with water (20 ml) followed bybrine, dried over anhydrous sodiumsulphate and concentrated using rotaryevaporator. The resulting crude was purified by column chromatography toafford 4-(5-(tributylstannyl)pyrazin-2-yl)morpholine as pale yellowcolor liquid.

¹H NMR (400 MHz, CDCl₃): δ 1.36 (s, 10H), 1.58 (s, 6H), 1.63 (s, 6H),1.67 (s, 6H), 3.57 (s, 4H), 3.85 (s, 4H), 8.13 (s, 1H), 8.36 (s, 1H).

Step-3

To a stirred solution of intermediate4-(5-(tributylstannyl)pyrazin-2-yl)morpholine (0.25 g) and G-2-In (0.38g) taken in dry xylene under nitrogen atmosphere, copper (I) iodide (10mg) was added. The reaction mixture was degasified using nitrogen andPd(PPh₃)₄ (0.065 g) was added. The reaction mixture was refluxed for 24hours concentrated under vacuum to remove the solvent. The crude waspurified by column chromatography using MeOH/CHCl₃ (1:9) as eluent toafford G-2b as white solid product.

¹H NMR (400 MHz, DMSO-d₆): δ 3.16 (s, 2H), 3.42 (s, 3H), 3.63, 3.68,3.75 (3s, 11H), 4.04 (s, 3H), 7.57-7.7 (m, 6H), 8.1, 8.19, 8.32 (3s,3H), 9.09 (s, 1H).

LCMS: 596.1 (M⁺+1).

HPLC: 92% (0.1% TFA/ACN; Column: C18 BDS, 4.6×250 mm).

Preparation of G-2c

Step-1

To sodium hydride (0.20 g) in THF (15 ml), imidazole (0.57 g) was addedand cooled to 0° C. To the above mixture 2,3-dibromopyrazine (2 g) wasadded and entire reaction mixture was allowed to reflux for overnight.The reaction mixture was quenched with water 5 ml volatiles were removedunder vacuum. The resulting crude mass was purified by columnchromatography to afford 2-bromo-5-(1H-imidazol-1-yl)pyrazine as pureproduct.

¹H NMR (400 MHz, CDCl₃): δ 7.30 (s, 1H), 7.65 (s, 1H), 8.44 (s, 1H),8.58 (s, 1H), 8.60 (s, 1H).

Step-2

To compound 2-bromo-5-(1H-imidazol-1-yl)pyrazine (0.25 g) taken in dryxylene, hexa-n-butyl di tin (0.615 ml) was added. The reaction mixturewas degasified under argon atmosphere for 3-5 times. To that tetrakis(triphenyl phosphine) palladium (0.128 g) was added and furtherdegasified under argon atmosphere for 3-5 times. The reaction mixturewas stirred under reflux conditions for overnight. The reaction mixturewas cooled room temperature, diluted with ethyl acetate and filteredthrough celite bed. The filtrate was concentrated and purified by columnchromatography to afford2-(1H-imidazol-1-yl)-5-(tributylstannyl)pyrazine as pale yellow colorliquid.

¹H NMR (400 MHz, CDCl₃): δ 1.36 (s, 10H), 1.58 (s, 6H), 1.63 (s, 6H),1.67 (s, 6H), 3.57 (d, 1H), 4.45 (d, 1H), 4.65 (s, 1H), 8.13 (s, 1H),8.36 (s, 1H).

Step-3

To a stirred solution of intermediate2-(1H-imidazol-1-yl)-5-(tributylstannyl)pyrazine (0.25 g) and G-2-In(0.38 g) taken in dry xylene under nitrogen atmosphere, copper (I)iodide (10 mg) was added. The reaction mixture was degasified usingnitrogen and Pd(PPh₃)₄ (0.065 g) was added. The reaction mixture wasrefluxed for 24 hours concentrated under vacuum to remove the solvent.The crude was purified by column chromatography using MeOH/CHCl₃ (1:9)as eluent to afford G-2c as white solid product.

¹H NMR (400 MHz, DMSO-d₆): δ 3.17 (t, 2H, J=8 Hz), 3.44 (t, 2H, J=4 Hz),3.69 (t, 2H, J=6 Hz), 4.04 (s, 3H), 7.24 (bs, 1H), 7.56-7.71 (m, 5H),8.12 (d, 1H, J=8 Hz), 8.26 (s, 2H), 8.73 (bs, 1H), 9.18 (s, 1H), 9.48(s, 1H), 12.65 (s, 1H).

LCMS: 575.2 (M⁺−1).

HPLC: 90.6% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Preparation of Compound G-3a and G-3b

Step-1

To 1-(3-iodopyridin-2-yl)piperazine (0.5 g) taken in dry toluene (10ml), added phenyl boronic acid (0.25 g) under nitrogen atmosphere. Toreaction mixture was added Pd(PPh₃)₄ (10 mg) and a solution of sodiumcarbonate (0.3 g) in water (2 ml). Reaction mixture was bubbled withNitrogen gas for about 10 min and refluxed for over-night. Reactionmixture was cooled to r.t and diluted with EtOAC, washed with 10% NaHCO₃and brine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using EtOAc/Hexane (2:8) as eluent to affordG-3-In as brown viscous liquid.

¹H NMR (400 MHz, CDCl₃): δ 3.06 (d, 4H), 3.14 (d, 4H), 6.94 (s, 1H),7.31 (s, 1H), 7.38-7.68 (m, 5H), 8.25 (s, 1H).

LCMS: 239.9 (M⁺+1).

Step-2

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.18 g), G-3-In (0.1 g), TBTU (0.15 g) and Hunig's base (0.15 ml)were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-3a asyellow solid.

¹H NMR (400 MHz, CDCl₃): δ 2.56 (s, 3H), 3.15 (s, 2H), 3.28 (s, 2H),3.44 (s, 2H), 3.71 (s, 2H), 4.04 (s, 3H), 7.0 (t, 1H, J=6 Hz), 7.34 (t,1H, J=6 Hz), 7.44 (t, 2H, J=6 Hz), 7.53 and 7.57 (2×d, 3H, J=8 Hz and 4Hz), 7.72 (s, 1H), 8.17 (d, 1H, J=2 Hz), 8.25 (d, 1H, J=2 Hz), 9.09 (s,1H), 11.03 (s, 1H).

¹³C NMR (400 MHz, CDCl₃): δ 14.16, 41.12, 45.72, 48.49, 49.09, 56.93,115.86, 117.62, 121.29, 123.11, 124.14, 127.51, 127.74, 127.89, 128.92,136.44, 141.32, 149.66, 162.2, 166.47, 185.64.

LCMS: 523.1 (M⁺+1).

HPLC: 97.7% (NH₄OAc/ACN; Column: C18 XDB, 250×4.6 mm).

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.18 g), G-In-3 (0.1 g), TBTU (0.15 g) and Hunig's base (0.15 ml)were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-3b asyellow solid.

¹H NMR (400 MHz, CDCl₃): δ 3.15 (t, 2H, J=4 Hz), 3.29 (t, 2H, J=6 Hz),3.49 (d, 2H, J=8 Hz), 3.73 (t, 2H, J=4 Hz), 7.01 (d, 1H, J=8 Hz), 7.36(d, 1H, J=8 Hz), 7.45 (t, 2H, J=8 Hz), 7.54 and 7.57 (dd, 3H, J=8 Hz and4 Hz), 7.93 (s, 1H), 8.14 (s, 1H), 8.25 (d, 1H, J=4 Hz), 8.33 (d, 1H,J=4 Hz), 8.76 (s, 1H), 11.22 (s, 1H).

LCMS: 497.1 (M⁺+1).

HPLC: 95.7% (NH₄OAc/ACN; Column: C18 XDB, 250×4.6 mm).

Preparation of Compound G-4a, G-4b, G-4c and G-4d

Step-1

To a stirred solution of cyano intermediate G-4-In-1 (300 mg) taken indry dichloromethane (10 ml) under nitrogen added N-dichloromethyleneN,N-dimethyl ammonium chloride (0.39 g) at rt under nitrogen. Thereaction mixture is allowed to stir at r.t. for 15 minutes. The reactionmixture was allowed to reflux at 50° C. for one hour. The reactionmixture was cooled to room temperature and added phenyl hydrazine (0.168g), triethyl amine (0.6 ml) in dichloromethane (5 ml) drop wise for onehour. The reaction mixture was allowed to stir at room temperature for 2hours, and then allowed to reflux at 55° C. for one hour. The reactionmixture was allowed to cool to −10° C. and added water (10 ml) andconcentrated KOH (2 g in 5 ml) and allowed to stir for 15 minutes at−10° C. The reaction mixture was extracted with dichloromethane (5×20ml). The combined organic layer was dried over anhydrous sodium sulphateand concentrated under vacuum. The resulting crude mixture of G-4-In-2and G-4-In-3 was purified by flash column chromatography usinghexane/ethyl acetate (2:8) as eluent to afford pure G-4-In-2 andG-4-In-3 as pale yellow liquids.

¹H NMR (400 MHz, CD₃OD): δ 1.45 (s, 9H), 2.95 (s, 6H), 3.09 (t, 4H, J=4Hz), 3.44 (bs, 4H), 7.38 (t, 1H, J=8 Hz), 7.51 (t, 2H, J=8 Hz), 7.62 (d,2H, J=8 Hz).

LCMS: 373 (M⁺+1).

HPLC: 97.6% (0.1% HCOOH/ACN; Column: Genesis C18, 4.6×50 mm).

Step-2

BOC protected amine G-4-In-2 (500 mg) dissolved in dry dichloromethane(10 ml) and TFA (5 ml) was added to it at 0° C. The reaction mixture wasallow reach at r.t. and stirred for over-night. The volatiles werecompletely removed under reduced pressure and the resulting crude wasdiluted with dichloromethane (10 ml). The organic layer was washed withsaturated NaHCO₃ (2×10 ml) and brine (20 ml) and dried over Na₂SO₄.Evaporation of solvent gave the desired amine In-4-In-4, which was usedfor the next reaction without any purification.

¹H NMR (400 MHz, DMSO-d₆): δ 2.68 (s, 6H), 2.73 (m, 4H), 3.17 (t, 4H,J=4 Hz), 7.31 (m, 1H), 7.48 (m, 4H).

¹³C NMR (DMSO-d6): δ 40.21 (2C), 41.29 (2C), 45.37, 47.06, 123.57 (2C),127.09, 129.57 (2C), 139.3, 158.16, 162.97.

LCMS: 273 (M⁺+1).

HPLC: 97.5% (0.1% TFA/ACN; Column: C18 BDS, 4.6×50 mm).

Step-3

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml) added amine G-4-In-4 (0.099 g), TBTU(0.178 g) and DIPEA (0.15 ml) were combined in. The reaction mixture wasstirred at r.t. for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. Resulting oilwas diluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under rotary evaporator. The resulting semi solid waspurified by column chromatography using MeOH/CHCl₃ (0.5:9.5) as eluentto afford G-4a as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.85 (s, 6H), 3.06 (bs, 2H), 3.17 (bs, 2H),3.49 (bs, 2H), 3.71 (bs, 2H), 7.30 (t, 1H, J=8 Hz), 7.47 (t, 2H, J=8Hz), 7.65 (d, 2H, J=8 Hz), 8.10 (s, 1H), 8.35 (s, 1H), 9.01 (s, 1H),13.05 (s, 1H).

LCMS: 530.1 (M⁺+1).

HPLC: 95.9% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Step-4

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml) added amine G-4-In-4 (0.090 g), TBTU(0.117 g) and DIPEA (0.15 ml) were combined in. The reaction mixture wasstirred at r.t. for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃and brine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (0.5:9.5) as eluent to affordG-4-b as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (s, 3H), 2.87 (s, 6H), 3.07 (bs, 2H),3.16 (bs, 2H), 3.43 (bs, 2H), 3.69 (bs, 2H), 3.99 (s, 3H), 7.30 (t, 1H,J=8 Hz), 7.48 (t, 2H, J=8 Hz), 7.66 (d, 2H, J=8 Hz), 7.89 (s, 1H), 8.22(s, 1H), 9.24 (s, 1H), 12.39 (s, 1H).

LCMS: 556.1 (M⁺+1), 554.4 (M⁺−1).

HPLC: 98.5% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Step-5

To BOC protected amine G-4-In-3 (500 mg) dissolved in drydichloromethane (10 ml), TFA (5 ml) was added to it at 0° C. Thereaction mixture was allowed reach at r.t. and stirred for over-night.The volatiles were completely removed under reduced pressure and theresidue was diluted with dichloromethane (10 ml). The organic layer waswashed with saturated NaHCO₃ (2×10 ml) and brine (20 ml). The organiclayer was dried over Na₂SO₄ and concentrated to dryness to afford amineG-4-In-5, which was used in the next step without any purification.

¹H NMR (400 MHz, DMSO-d₆): δ 2.68 (s, 6H), 2.75 (bs, 4H), 3.18 (bs, 4H),7.31 (m, 1H), 7.49 (m, 4H).

¹³C NMR (DMSO-d₆): δ 40.21 (2C), 41.29 (2C), 45.37, 47.06, 123.57 (2C),127.09, 129.57 (2C), 139.3, 158.16, 162.97.

LCMS: 272.9 (M⁺+1).

HPLC: 97.5% (0.1% TFA/ACN; Column: C18 BDS, 4.6×50 mm).

Step-6

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), amine G-4-In-5 (0.099 g), TBTU (0.127g) and DIPEA (0.15 ml) were added. The reaction mixture was stirred atr.t. for over night. The mixture was quenched with methanol (10 ml) andvolatiles were removed under reduced pressure. The oil was diluted withethyl acetate (50 ml), washed with 10% NaHCO₃ and brine. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated using rotaryevaporator. The resulting crude was purified by column chromatographyusing MeOH/CHCl₃ (0.5:9.5) as eluent to afford G-4-c as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.69 (s, 6H), 3.28 (s, 3H), 3.41 (d, 2H,J=4 Hz), 3.47 (d, 2H, J=4 Hz), 3.73 (t, 2H, J=6 Hz), 7.32 (m, 1H),7.44-7.50 (m, 4H), 8.12 (s, 1H), 8.32 (d, 1H, J=4 Hz), 8.36 (s, 1H),9.01 (d, 1H, J=4 Hz).

LCMS: 530.2 (M⁺+1).

HPLC: 96.3% (0.1% TFA/ACN; Hypersil BDS C18, 4.6×50).

Step-7

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), amine G-4-in-5 (0.090 g), TBTU (0.117g) and DIPEA (0.15 ml) were added. The reaction mixture was stirred atr.t. for over night. The mixture was quenched with methanol (10 ml) andsolvents were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude was purified by column chromatography usingMeOH/CHCl₃ (0.5:9.5) as eluent to afford G-4d as solid product.

¹H NMR (400 MHz, DMSO-d₆): δ 2.49 (s, 3H), 2.70 (s, 6H), 3.28 (bs, 2H),3.42 (bs, 4H), 3.70 (bs, 2H), 3.99 (s, 3H), 7.32 (m, 1H), 7.49 (m, 4H),7.89 (s, 1H), 8.24 (s, 1H), 9.24 (s, 1H), 12.39 (s, 1H).

LCMS: 556.1 (M⁺+1), 554.4 (M⁺−1).

HPLC: 99.5% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Preparation of Compound 5a and 5b Preparation of Intermediate G-5-In

Step-1

A one liter three necked round bottom flask was charged withBoc-piperazine (20 g), dry potassium carbonate (44.5 g) and dry DMF (150ml) under nitrogen atmosphere. The reaction mixture was cooled to 0° C.and bromoacetophenone (23.5 g) was added into the reaction mixture veryslowly. The reaction mixture was stirred at room temperature forovernight. The progress of reaction was monitored by TLC. Afterconsumption of starting material, ice-cold water (200 ml) was added toreaction mixture. The precipitated white solid was filtered, washed withwater (4×50 ml) and dried to afford tert-butyl4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate as pure product.

¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 2.59 (s, 4H), 3.52-3.54 (s,4H), 3.87 (s, 2H), 7.27-7.29 (m, 1H).

Step-2

To the compound tert-butyl4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate (18 g) taken in roundbottom flask, Bredereck's reagent (11.33 g) was added very slowly undernitrogen atmosphere. The reaction mixture was stirred at 55° C. forover-night. The progress of reaction was monitored by TLC. Afterconsumption of starting material, diethyl ether was added to thereaction mixture. The resulting solid was filtered and dried underreduced pressure to afford tert-butyl4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylateas pure product.

¹H NMR (400 MHz, DMSO-d₆): δ 1.36-1.41 (s, 9H), 2.87 (s, 4H), 3.01 (s,6H), 3.33 (s, 4H), 6.53 (s, 1H), 7.32-7.42 (m, 5H).

Step-3

To the compound tert-butyl4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate(4 g) dissolved in ethanol (40 ml), and hydrazine hydrate (1.17 g) wasadded and the reaction mixture was refluxed for 6 hrs with vigorousstirring. The progress of reaction was monitored by TLC. Afterconsumption of starting material, the reaction mixture was cooled toroom temperature and concentrated under reduced pressure to affordtert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate.

¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 2.81 (s, 4H), 3.48-3.55 (m,4H), 7.27-7.43 (m, 5H), 7.94 (s, 1H), 8.3 (bs, 1H).

Step-4

To BOC protected amine tert-butyl4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (1 g) dissolved indry dichloromethane (10 ml), TFA (5 ml) was added at 0° C. The reactionmixture was allowed to reach room temperature and stirred forover-night. The volatiles were completely removed and resulting residuewas diluted with dichloromethane (20 ml). The organic layer was washedwith saturated NaHCO₃ (2×10 ml), brine, dried over Na₂SO₄. Evaporationof solvent gave desire amine G-5-In, which was used for the nextreaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 2.81 (s, 4H), 3.48-3.55 (m, 4H), 7.27-7.43(m, 5H), 7.94 (s, 1H), 8.3 (bs, 1H).

LCMS: 228.29 (M⁺+1).

HPLC: 99.64% (TFA/ACN; Column: C18 BDS, 4.6×50 mm).

Preparation of G-5a

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (90 mg) in dry DMF (5 ml), G-5-In (75 mg), TBTU (0.117 g) and DIPEA(0.1 ml) were added. The reaction mixture was stirred at r.t. for overnight. The reaction was quenched with methanol (10 ml) and the volatileswere removed under reduced pressure. The resulting oil was diluted withethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated using rotaryevaporator. The resulting crude was purified by column chromatographyusing MeOH/CHCl₃ (2:8) as eluent to afford G-5a as yellow color solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.78 (d, 2H), 2.87 (d, 2H), 3.53 (d, 2H),3.77 (d, 2H), 7.27-7.63 (m, 5H), 8.0 (s, 1H), 8.12 (s, 1H), 8.34 (d,2H), 9.01 (s, 1H), 12.62 (bs, 1H), 13.06 (bs, 1H).

¹³C NMR (DMSO-d₆): δ 54.14, 51.83, 52.13, 112.53, 122.59, 121.18,121.39, 122.37, 125.31, 125.58, 126.36, 127.84, 128.24, 130.96, 133.24,133.58, 140.85, 150.42, 153.0, 164.92, 183.79.

LCMS: 486.1 (M⁺+1).

HPLC: 98.28% (H₂O/ACN; Column: C18 XDB, 4.6×250 mm).

Preparation of G-5b

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), G-5-In (75 mg), TBTU (0.117 g) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using MeOH/CHCl₃ (2:8) as eluent to afford G-5b as yellowcolor solid

¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (s, 3H), 2.78 (m, 2H), 2.87 (m, 2H),3.35 (m, 2H), 3.49 (m, 2H), 4.01 (s, 3H), 7.27 (m, 5H), 7.40-8.23 (m,3H), 9.24 (s, 1H), 12.39 (bs, 1H), 12.63 (bs, 1H).

¹³C NMR (DMSO-d₆): δ 14.44, 46.02, 52.82, 52.95, 57.34, 114.71, 121.57,123.27, 124.24, 126.20, 127.35, 128.85, 130.11, 139.18, 142.67, 149.77,161.85, 166.67, 186.09.

LCMS: 512.0 (M⁺+1).

HPLC: 97.27% (H₂O/ACN; Column: C18 XDB, 4.6×250 mm).

Preparation of Compound G-6a and G-6b Preparation of Intermediate G-In-6

Step-1

To sodium hydride (0.1 g) taken in a dry 100 ml 3-necked round bottomflask cooled to 0° C., dry dimethylformamide (2 ml) was added. To theabove mixture, compound tert-butyl4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g) in DMF (2ml) was slowly added at 0° C. After 30 min,2-chloro-N,N-dimethylethylamine (200 mg) in DMF (1 ml) was added to theabove mixture. Reaction mixture was allowed to stir at room temperaturefor overnight, quenched with ice and extracted with ethyl acetate. Theorganic layer was washed with water (10 ml), brine and dried oversodiumsulphate. The organic layer was filtered and concentrated underreduced pressure. The resulting crude product was purified by columnchromatography using 6% Ethyl acetate in hexane as eluant affordtert-butyl4-(1-(2-(dimethylamino)ethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylateas half white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.49 (s, 9H), 2.33 (s, 6H), 2.83-2.85 (t,4H), 2.87 (t, 2H), 3.53 (t, 4H), 4.25 (t, 2H), 7.27-7.29 (m, 1H), 8.01(s, 1H).

Step-2

BOC protected amine tert-butyl4-(1-(2-(dimethylamino)ethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate(300 mg) dissolved in dry dichloromethane (5 ml) and ethereal solutionof HCl (10 ml) was added to it at 0° C. The reaction mixture was allowedreach at r.t. and stirred for an hour. The reaction mixture wasneutralized with saturated sodium bicarbonate solution and extractedwith dichloromethane (3×10 ml). The combined organic layer was driedover sodiumsulphate, filtered and concentrated under reduced pressure.The resulting crude product G-6-In was taken for next step withoutfurther purification.

¹H NMR (400 MHz, CDCl₃): δ 2.33 (s, 6H), 2.83-2.85 (t, 4H), 2.87 (t,2H), 3.53 (t, 4H), 4.25 (t, 2H), 7.27-7.29 (m, 1H), 8.01 (s, 1H).

Preparation of G-6a

To2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.15 g) taken in dry DMF (3 ml), amine G-6-In (0.1 g), TBTU (0.219g, 0.67 m mol) and Hunig's base (0.2 ml) were added. The reactionmixture was stirred at r.t. for over night. The mixture was quenchedwith methanol (10 ml) and the volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml) andwashed with 10% NaHCO₃ (2×20 ml) and brine (20 ml). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.The resulting crude was purified by Column chromatography usingMeOH/CHCl₃ (1:9) as eluent to afford G-6a as solid product.

¹H NMR (CDCl₃): δ 2.58 (s, 8H), 2.8-3.0 (m, 5H), 3.35 (bs, 2H), 3.61 (s,2H), 3.86 (s, 2H), 4.1 (s, 2H), 4.55 (s, 2H), 7.32 (m, 1H), 7.41 (m,3H), 7.97 (d, 2H), 8.24 (s, 1H), 9.12 (s, 1H).

LCMS: 583.3 (M⁺+1).

HPLC: 94.1% (Water/ACN; Column: C 18, XDB, 4.6×250 mm).

Preparation of G-6b

To2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.15 g) taken in dry DMF (3 ml), amine G-6-In (0.1 g), TBTU (0.219g) and Hunig's base (0.2 ml) were added. The reaction mixture wasstirred at r.t. for over night. The mixture was quenched with methanol(10 ml) and the volatiles were removed under reduced pressure. Theresulting oil was diluted with ethyl acetate (50 ml) and washed with 10%NaHCO₃ (2×20 ml) and brine (20 ml). The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by Column chromatography using MeOH/CHCl₃ (1:9) aseluent to afford G-6b as solid product.

¹H NMR (DMSO-d₆): δ 2.31 (s, 6H), 2.80 (m, 6H), 3.53 (s, 2H), 3.76 (s,2H), 4.18 (t, 2H, J=6 Hz), 7.24 (t, 1H, J=6 Hz), 7.38 (t, 2H, 8 Hz),7.67 (s, 1H), 7.96 (d, 2H, J=8 Hz), 8.09 (s, 1H), 8.25 (s, 1H), 8.31 (s,1H), 9.02 (s, 1H).

LCMS: 557.1 (M⁺+1).

HPLC: 99% (0.1% HCOOH/ACN; Column: Genesis C18, 50×4.6 mm, 3μ).

Preparation of Compound G-7a and G-7b Preparation of Intermediate G-7-In

Step-1

To sodium hydride (0.1 g) taken in a dry 100 ml 3-necked round bottomflask cooled to 0° C. dry DMF (2 ml) was added under nitrogen. To theabove mixture compound tert-butyl4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g) in DMF (2ml) was slowly added and allowed to stir at 0° C. for 30 minutes.2-Chloromethyl pyridine (300 mg) in DMF (1 ml) was slowly added to theabove mixture at 0° C. The reaction mixture was allowed to stir at roomtemperature for overnight and quenched with ice. The product wasextracted with ethyl acetate (3×10 ml). The combined organic layer waswashed with water, brine, dried over sodiumsulphate and concentratedunder reduced pressure. The resulting crude product was purified bycolumn chromatography using 6% ethyl acetate in hexane, to affordtert-butyl4-(3-phenyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)piperazine-1-carboxylateas half white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 2.80 (s, 4H), 3.53 (s, 4H),5.57 (s, 2H), 7.27-7.33 (m, 5H), 7.85-8.02 (m, 4H), 8.61 (s, 1H).

Step-2

To tert-butyl4-(3-phenyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)piperazine-1-carboxylate(300 mg) dissolved in dry dichloromethane (5 ml), ethereal solution ofHCl (10 ml) was added at 0° C. The reaction mixture was allowed to reachroom temperature and stirred for an hour. The reaction mixture wasneutralized with saturated sodium bicarbonate solution and extractedwith dichloromethane (3×10 ml). The combined organic layer was driedover sodiumsulphate, filtered and concentrated under reduced pressure.The resulting crude product G-7-In was taken for the next step with outfurther purification.

¹H NMR (400 MHz, CDCl₃): δ 2.80 (s, 4H), 3.53 (s, 4H), 5.57 (s, 2H),7.27-7.33 (m, 5H), 7.85-8.02 (m, 4H), 8.61 (s, 1H).

Preparation of G-7a

To2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.15 g) taken in dry DMF (3 ml), amine G-7-In (0.1 g), TBTU (0.219g) and Hunig's base (0.2 ml) were added. The reaction mixture wasstirred at r.t. for over night. The mixture was quenched with methanol(10 ml) and the volatiles were removed under reduced pressure. Theresulting oil was diluted with ethyl acetate (50 ml) and washed with 10%NaHCO₃ (2×20 ml) and brine (20 ml). The organic layer was dried overanhydrous Na₂SO₄ and concentrated using rotary evaporator. The resultingcrude was purified by Column chromatography using MeOH/CHCl₃ (1:9) aseluent to afford G-7a as solid product.

¹H NMR (DMSO-d₆): δ 2.77 (s, 2H), 2.87 (s, 2H), 3.49 (s, 3H), 3.74 (s,2H), 4.01 (s, 3H), 5.38 (s, 2H), 7.08 (d, 1H, J=8 Hz), 7.35 (m, 4H),7.79 (m, 2H), 7.89 (s, 1H), 7.96 (d, 2H, J=4 Hz), 8.23 (s, 1H), 8.53 (s,1H), 9.25 (s, 1H), 12.38 (bs, 1H).

LCMS: 603.2 (M⁺+1).

HPLC: 96% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm, 5μ).

Preparation of G-7b

To2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.15 g) taken in dry DMF (3 ml), amine G-7-In (0.1 g), TBTU (0.219g) and Hunig's base (0.2 ml) were added. The reaction mixture wasstirred at r.t. for over night. The mixture was quenched with methanol(10 mL) and the volatiles were removed under reduced pressure. Theresulting oil was diluted with ethyl acetate (50 ml) and washed with 10%NaHCO₃ (2×20 ml) and brine (20 ml). The organic layer was dried overanhydrous Na₂SO₄ and concentrated using rotary evaporator. The resultingcrude was purified by Column chromatography using MeOH/CHCl₃ (1:9) aseluent to afford G-7b as solid product.

¹H NMR (DMSO-d₆): δ 2.77 (s, 2H), 2.87 (s, 2H), 3.54 (s, 2H), 3.77 (s,2H), 5.37 (s, 2H), 7.08 (d, 1H, J=8 Hz), 7.32 (m, 4H), 7.76 (s, 2H),7.96 (d, 2H, J=8 Hz), 8.12 (s, 1H), 8.34 (d, 2H, J=12 Hz), 8.53 (s, 1H),9.02 (s, 1H).

HPLC: 98% (0.1% TFA/ACN; Column: Hypersil BDS C18, 5μ, 4.6×50 mm).

Preparation of Compound G-8a and G-8b Preparation of Intermediate G-8-In

Step-1

To a stirred solution of N-Boc piperazine (1 g) in dry THF (20 ml),triethylamine (3 ml), followed by chloroacetonitrile (5.02 ml) wereadded dropwise. The reaction mixture was allowed to stir at roomtemperature for overnight. The solvent was removed under vacuum andresidue was diluted ethyl acetate (20 ml). The organic layer wasconcentrated to dryness under reduced pressure to afford tert-butyl4-(cyanomethyl)piperazine-1-carboxylate, which was used for the nextreaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 1.47 (s, 9H), 2.55 (t, 4H, J=6 Hz), 3.49 (t,4H, J=4 Hz), 3.55 (s, 2H).

GC MS: 225

Step-2

To sodium hydride (0.1 g) taken in dry DMF (5 ml), under nitrogen,compound tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate (0.5 g) wasadded and allowed to stir at room temperature for half an hour.Benzaldehyde (280 mg) was added to the above reaction mixture andallowed to stir for 3 hours at room temperature. The reaction mixturewas quenched with ice water (50 ml) and extracted with ethyl acetate(3×10 ml). The combined organic layer was washed with brine (10 ml),dried over sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by column chromatography using MeOH:CH₂Cl₂ (0.5:9.5) as an eluent to afford tert-butyl4-(1-cyano-2-phenylvinyl)piperazine-1-carboxylate as pure product.

¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 3.09 (t, 4H, J=6 Hz), 3.56 (t,4H, J=4 Hz), 6.22 (s, 1H), 7.30 (d, 1H, J=12 Hz), 7.38 (d, 2H, J=8 Hz),7.55 (d, 2H, J=8 Hz).

Step-3

To a stirred solution of tert-butyl4-(1-cyano-2-phenylvinyl)piperazine-1-carboxylate (100 mg) taken in dryDMSO (2 ml) added sodium azide (0.2 g) and heated to 110° C. overnight.The reaction mixture was carefully quenched with water (10 ml) and thereaction mixture was extracted with dichloromethane (3×10 ml). Thecombined organic layer was washed with brine (10 ml), dried over sodiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by column chromatography using MeOH: CH₂Cl₂ (1:9) as aneluent to afford tert-butyl4-(5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate as whitesolid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.4 (s, 9H), 2.92 (d, 4H, J=4 Hz), 3.43 (m,4H), 7.33 (m, 1H, J=12 Hz and 16 Hz), 7.45 (t, 2H, 8 Hz), 7.85 (d, 2H,J=8 Hz), 14.32 (s, 1H).

Step-4

To tert-butyl 4-(5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate(500 mg) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was addedat 0° C. The reaction mixture was allowed to reach room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-8-In, which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 2.84 (2s, 8H), 7.32 (t, 1H, J=8 Hz), 7.45(t, 2H, J=6 Hz), 7.83 (d, 2H, J=8 Hz).

LCMS: 230.1 (M⁺+1).

Preparation of G-8a

Step-5

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), G-8-In (0.083 g), TBTU (0.128 g) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using MeOH/CHCl₃ (2:8) as eluent to afford G-8a as yellowcolor solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.99 (s, 2H), 3.09 (s, 2H), 3.57 (s, 2H),3.8 (s, 2H), 7.35 (d, 1H, J=8 Hz), 7.45 (t, 2H, J=6 Hz), 7.87 (d, 2H,J=8 Hz), 8.12 (s, 1H), 8.34 (d, 2H, J=16 Hz), 9.02 (s, 1H), 13.08 (s,1H), 14.4 (s, 1H).

LCMS: 487.1 (M⁺+1).

HPLC: 95.2% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Preparation of G-8b

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), G-8-In (0.076 g), TBTU (0.117 g) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using MeOH/CHCl₃ (2:8) as eluent to afford G-8b as anamorphous solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H), 2.99 (t, 2H, J=4 Hz), 3.1 (t,2H, J=6 Hz), 3.52 (t, 2H, J=4 Hz), 3.77 (t, 2H, J=6 Hz), 4.0 (s, 3H),7.34 (t, 1H, J=8 Hz), 7.46 (t, 2H, J=8 Hz), 7.88 (t, 3H, J=4 Hz), 8.23(s, 1H), 9.25 (s, 1H), 12.4 (bs, 1H), 14.5 (bs, 1H).

LCMS: 513.1 (M⁺+1).

HPLC: 90.39% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Preparation of Compound G-9a and G-9b

Sodium hydride (0.3 g) was taken in dry DMF (2 ml) and a solution of5-amino-1-phenyl-pyrazole (0.5 g) was added slowly at 0° C. The reactionmixture was stirred for 1 hour at room temperature. Again the reactionmixture was cooled at 0° C. and a solution of bis(2-chloroethylamine)hydrochloric (0.61 g) in DMF (2 ml) was added very slowly. The reactionmixture was allowed to stir over night at room temperature. The reactionmixture was quenched with cold water (5 ml) and extracted with ethylacetate (3×40 ml). Evaporation of solvent under reduced pressure gavecrude product, which, was purified by column chromatography usingMeOH/CHCl₃ (2:8) as eluent to afford G-9-In as pure solid product.

¹H NMR (400 MHz, DMSO-d₆): δ 2.36-3.06 (m, 8H), 5.95 (s, 1H), 7.29 (m,1H), 7.30-8.32 (m, 5H).

¹³C NMR (DMSO-d₆): δ 45.45, 52.50, 94.80, 122.58, 126.91, 129.47,140.16, 140.53, 152.63.

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-9-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-9a asyellow solid.

¹H NMR (400 MHz, CDCl₃): δ 2.57 (s, 3H), 2.93-2.94 (t, 2H), 3.02-3.04(t, 2H), 3.55-3.57 (t, 2H), 3.80-3.82 (t, 2H), 4.06 (s, 3H), 5.93 (s,1H), 7.27 (s, 1H), 7.31-7.46 (m, 5H), 7.80 (bs, 1H), 8.20 (s, 1H), 9.12(s, 1H), 11.06 (bs, 1H).

¹³C NMR (CDCl₃): δ 14.13, 41.03, 45.63, 50.77, 51.15, 56.97, 94.80,115.74, 121.38, 123.13, 124.15, 127.22, 129.11, 129.70, 136.51, 139.74,139.90, 141.28, 149.63, 150.74, 162.12, 166.39, 185.36.

LCMS: 512.1 (M⁺+1).

HPLC: 96.12% (H₂O/ACN; Column: C18 XDB, 4.6×250 mm).

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-9-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-9b asyellow solid.

¹H NMR (400 MHz, CD₃OD): δ 2.93-2.95 (t, 2H), 3.01-3.04 (t, 2H),3.57-3.59 (t, 1H), 3.79-3.81 (t, 1H), 6.10 (s, 1H), 7.41 (m, 1H),7.51-7.75 (m, 5H), 8.01 (s, 1H), 8.21 (s, 1H), 8.39 (s, 1H), 8.93 (s,1H).

¹³C NMR (DMSO-d₆): δ 31.13, 45.47, 51.06, 51.42, 95.85, 113.44, 113.50,122.34, 122.55, 122.72, 123.58, 126.27, 127.16, 129.61, 132.22, 134.42,140.16, 140.22, 142.83, 151.26, 151.47, 154.05, 166.08, 184.49.

LCMS: 486.1 (M⁺+1).

HPLC: 99.08% (HCOOH/ACN; Column: C18 XDB, 4.6×50 mm).

Preparation of G-10a and G-10b Preparation of Intermediate G-10-In

Step-1

To tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g)taken in dry toluene (50 ml) cooled to −10° C., trimethylaluminium wasadded slowly in dry toluene under nitrogen atmosphere. Reaction mixturewas allowed to warm to r.t. and a second lot of solution of tert-butyl4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g in 50 ml oftoluene) was added very slowly to it. The combined mixture was heated upto 55° C. for 30 minutes. A solution of ethyl benzoate (7.4 g in 50 mlof dry toluene) was added very-very slowly to the reaction mixture at55° C. over a period of 40 minutes. After the completion of addition,the reaction mixture was refluxed for over night. Reaction mixture wascooled to 0° C. and water (3×50 ml) was added. The combined mixture wasfiltered through celite pad. The filtrate was concentrated under reducedpressure and the resulting oil was purified by column chromatography toafford tert-butyl4-(2-phenyl-4,5-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate as apure product.

¹H NMR (400 MHz, CD₃OD): δ 1.45 (s, 9H), 1.71-1.75 (m, 4H), 2.62 (m,2H), 3.85 (m, 1H), 3.95 (m, 4H), 4.91 (m, 2H), 7.56-7.63 (m, 5H).

LCMS: 330.1 (M⁺+1).

Step-2

To tert-butyl4-(2-phenyl-4,5-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate (2.2g) dissolved in dry dichloromethane (100 ml), TFA (50 ml) was added at0° C. The reaction mixture was allowed to reach room temperature andstirred for over-night. The volatiles were removed and the residue wasdiluted with dichloromethane. The organic layer was washed withsaturated NaHCO₃ (2×50 ml), brine (40 ml) dried over Na₂SO₄. Evaporationof solvent afforded desired amine G-10-In which was used for the nextstep without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 1.88-1.91 (m, 2H), 2.15-2.21 (m, 2H),2.85-2.90 (m, 2H), 3.22-3.25 (m, 2H), 3.88-4.05 (m, 5H), 7.46-7.74 (m,5H), 10.98 (bs, 1H).

¹³C NMR (DMSO-d₆): δ 26.05, 42.12, 43.31, 45.48, 51.19, 123.20, 129.07,129.83, 133.54, 166.19.

LCMS: 229.9 (M⁺+1).

Preparation of G-10a

To2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.09 g) in dry DMF (5 mL), amine G-10-In (0.08 g), TBTU (0.12 g)and Hunig's base (0.2 ml) were added. The reaction mixture was stirredat r.t. for over night. The mixture was quenched with methanol (10 ml)and solvents were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The resulting semi-solid was purified by columnchromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-10a assolid.

¹H NMR (400 MHz, CD₃OD): δ 2.22 (m, 4H), 3.77 (m, 4H), 4.2 (m, 2H), 4.6(m, 2H), 7.70 (m, 5H), 8.01 (s, 1H), 8.43 (s, 1H), 8.5 (s, 1H), 8.93 (s,1H).

¹³C NMR (CD₃OD): δ 30.14, 30.89, 41.25, 45.92, 46.23, 48.36, 79.47,114.44, 124.50, 124.69, 124.96, 126.02, 126.30, 128.26, 129.21, 129.56,130.32, 132.84, 134.46, 147.54, 153.38, 155.95, 168.48, 185.58.

LCMS: 487.1 (M⁺+1).

HPLC: 98.14% (NH₄OAc/ACN; Column: C18 XDB, 4.6×250 mm).

Preparation of G-10b

To2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.1 g) taken in dry DMF (5 ml), G-10-In (0.076 g), TBTU (0.117 g)and Hunig's base (0.2 ml) were added. The reaction mixture was stirredat r.t. for over night. The mixture was quenched with methanol (10 ml)and the volatiles were removed under reduced pressure. The resulting oilwas diluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated using rotary evaporator. The crude was purified by columnchromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-10b as solidproduct.

¹H NMR (400 MHz, CD₃OD): δ 2.55 (s, 3H), 2.76-2.81 (bs, 1H), 3.03-3.09(t, 1H), 3.78-3.97 (m, 6H), 4.65 (s, 3H), 4.90 (d, 1H), 7.57-7.58 (d,5H), 7.83 (s, 1H), 8.29 (s, 1H), 9.22 (s, 1H).

¹³C NMR (CD₃OD): δ 13.73, 30.31, 30.77, 41.48, 45.62, 46.36, 48.36,48.58, 54.70, 57.35, 115.64, 122.02, 124.98, 127.28, 129.17, 130.08,130.54, 131.53, 132.05, 141.34, 143.24, 151.20, 162.78, 168.53, 168.59,187.35.

LCMS: 513.1 (M⁺+1).

HPLC: 95.26% (NH₄OAc/ACN; Column: C18 XDB, 4.6×250 mm).

Preparation of G-11a and G-11b Preparation of Intermediate G-11-In

Step-1

Tert-butyl-4-(2-phenyl-4,5-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate(0.1 g) and nickel peroxide was dissolved in dry benzene (20 ml) andrefluxed at 100° C. for over-night. Reaction mixture was allowed to cometo room temperature, filtered through a celite pad and washed with CHCl₃(2×20 ml). The organic solvent removed under reduced pressure gave anoil, which was purified by column chromatography using ethyl acetate.Evaporation of solvent gave pure product, tert-butyl4-(2-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate.

¹H NMR (400 MHz, CD₃OD): δ 1.47 (s, 9H), 1.89-1.96 (m, 4H), 3.0 (m, 2H),4.23 (m, 2H), 4.32 (d, 1H), 7.08 (d, 1H), 7.38 (s, 1H), 7.52-7.55 (m,5H).

LCMS: 328.1 (M⁺+1).

Step-2

tert-Butyl 4-(2-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (600mg) dissolved in dry dichloromethane (10 ml) and TFA (5 ml) was added toit at 0° C. The reaction mixture was allowed stir at room temperatureand stirred for over-night. The volatiles were completely removed andthe residue was diluted with dichloromethane. The organic layer waswashed with saturated NaHCO₃ (2×10 ml) and brine (20 ml), dried overNa₂SO₄. Evaporation of solvent afforded desired amine G-11-In which wasused for the next step without further purification.

¹H NMR (400 MHz, CD₃OD): δ 1.88-2.02 (m, 4H), 2.64 (m, 2H), 3.31 (m,2H), 4.91 (m, 1H), 7.09 (d, 1H), 7.37 (d, 1H), 7.47-7.56 (m, 5H).

¹³C NMR (CD₃OD): δ 34.83, 43.73, 46.16, 55.27, 62.18, 118.47, 128.36,128.47, 128.64, 129.52, 129.61, 130.33, 130.46, 148.59.

Preparation of G-11a

To2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.1 g dissolved in dry DMF (5 m), amine G-11-In (0.074 g), TBTU(0.12 g) and Hunig's base (0.2 ml) were added and allowed to stir atr.t. for over night. The mixture was quenched with methanol (10 ml) andthe volatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ (2×20 ml)and brine (20 ml). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified byColumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-11aas solid product.

¹H NMR (400 MHz, CD₃OD): δ 2.05-2.17 (m, 4H), 2.94 (bs, 1H), 3.27-3.32(bs, 1H), 3.95 (d, 1H), 4.73 (bs, 1H), 4.90 (d, 1H), 7.11 (s, 1H),7.44-7.92 (m, 5H), 8.01 (s, 1H), 8.21 (s, 1H), 8.41 (s, 1H), 8.92 (s,1H).

¹³C NMR (CD₃OD): δ 33.69, 34.54, 41.73, 46.44, 55.03, 114.80, 114.85,118.64, 123.64, 127.23, 127.51, 128.92, 130.02, 130.40, 130.60, 131.52,134.80, 141.91, 148.70, 167.63, 185.78.

LCMS: 485.1 (M⁺+1).

HPLC: 95.38% (0.1% TFA/ACN; Column: C18 BDS, 4.6×250 mm).

Preparation of G-11b

To2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.1 g) dissolved in dry DMF (5 ml), amine G-11-In (0.079 g), TBTU(0.11 g) and Hunig's base (0.1 ml) were added and the reaction mixturewas stirred at r.t. for over night. The mixture was quenched withmethanol (10 ml) and the volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml) and washed with10% NaHCO₃ (2×20 ml) and brine (20 ml). The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by Column chromatography using MeOH/CHCl₃ (1:9) aseluent to afford G-11b as solid product.

¹H NMR (400 MHz, CD₃OD): δ 2.05-2.20 (m, 4H), 2.55 (s, 3H), 2.94-3.20(t, 1H), 3.23-3.27 (bs, 1H), 3.87 (d, 1H), 4.06 (s, 3H), 4.51 (bs, 1H),4.91 (d, 1H), 7.11 (s, 1H), 7.43 (s, 1H), 7.53-7.55 (m, 5H), 7.81 (s,1H), 8.28 (s, 1H), 9.20 (s, 1H).

¹³C NMR (CD₃OD): δ 13.77, 33.80, 34.32, 41.68, 46.43, 55.09, 57.38,115.74, 118.62, 122.15, 124.64, 125.30, 128.96, 130.01, 130.40, 130.56,131.03, 131.56, 139.49, 142.80, 148.70, 151.08, 162.93, 168.46, 187.54.

LCMS: 511.2 (M⁺+1).

HPLC: 95.35% (NH₄OAc/ACN; Column: C18 XDB, 250×4.6 mm).

Preparation of Compound G-12a and G-12b Preparation of IntermediateG-12-In

Step-1

To a stirred solution of N-phenyl ethylenediamine (2 g) in absolutealcohol (30 ml), carbon disulphide (2.23 g) was added under nitrogen.The reaction mixture was refluxed for three hours and was brought toroom temperature. The resulting white solid (thioamide intermediate) wasfiltered, dried and taken for the next step without furtherpurification.

To a stirred solution of thioamide intermediate (2 g) in dry methanol(20 ml), methyl iodide (3.1 g) was added. The reaction mixture wasrefluxed for three hours. The volatiles were removed under vacuum andthe resulting white color solid,2-(methylthio)-1-phenyl-4,5-dihydro-1H-imidazole, was taken for the nextstep without further purification.

¹H NMR (400 MHz, DMSO-d6): δ 2.65 (s, 3H), 4.06 (t, 2H), 4.38 (t, 2H),7.46-7.57 (m, 5H).

LCMS: 192.9 (M⁺+1).

Step-2

To a stirred solution of2-(methylthio)-1-phenyl-4,5-dihydro-1H-imidazole (100 mg) in toluene (5ml), N-Boc piperazine (0.48 g) was added and whole reaction mixture wasrefluxed for overnight. The solvent was removed completely and ethylacetate was added to the residue. The resulting white solid, tert-butyl4-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)piperazine-1-carboxylate, wasfiltered, dried and used for the next reaction without furtherpurification.

¹H NMR (400 MHz, CD₃OD): δ 1.49 (s, 9H), 3.17 (m, 4H), 3.32 (m, 4H),3.89 (t, 2H), 4.25 (t, 2H), 7.40-7.56 (m, 5H).

LCMS: 331.1 (M⁺+1).

Step-3

To tert-butyl4-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)piperazine-1-carboxylate (500mg) taken in dry dichloromethane (10 ml), TFA (5 ml) was added at 0° C.The reaction mixture was allowed reach at room temperature and stirredfor over-night. The volatiles were removed using reduced pressure andthe residue was diluted with dichloromethane (10 ml). The organic layerwas washed with saturated NaHCO₃ (2×10 ml), brine (20 ml) and was driedover Na₂SO₄. Evaporation of solvent gave desire amine G-12-In which wastaken for the next reaction without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 2.52 (m, 4H), 3.06 (m, 4H), 3.66 (t, 2H),4.04 (t, 2H), 7.18-7.44 (m, 5H).

LCMS: 230.9 (M⁺+1).

Preparation of G-12a

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (50 mg) in dry DMF (5 ml), amine G-12-In (41 mg), TBTU (64 mg) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-12a asyellow color solid.

¹H NMR (DMSO-d₆): δ 3.21 (d, 2H), 3.34 (m, 4H), 3.66 (d, 2H), 3.73-3.77(t, 2H), 4.14-4.18 (t, 2H), 7.30-7.50 (m, 5H), 8.11 (s, 1H), 8.28 (s,1H), 8.35 (s, 1H), 9.0 (s, 1H).

LCMS: 488.1 (M⁺+1).

HPLC: 99.66% (0.1% TFA/ACN; Column: C18 BDS, 4.6×50 mm).

Preparation of G-12b

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (50 mg) in dry DMF (5 ml), amine G-12-In (38 mg), TBTU (0.117 g)and DIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t.for over night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-12b asyellow color solid.

¹H NMR (DMSO-d₆): δ 2.72 (s, 3H), 3.06 (d, 2H), 3.18 (d, 2H), 3.31 (t,2H), 3.33-3.62 (m, 4H), 3.90 (t, 2H), 3.95 (s, 3H), 7.02-7.26 (m, 5H),7.82 (s, 1H), 8.18 (s, 1H), 9.28 (s, 1H), 11.89 (bs, 1H).

LCMS: 514.2 (M⁺+1).

HPLC: 99.25% (NH₄OAc/ACN; Column: C18 XDB, 250×4.6 mm).

Preparation of G-13a and G-13b

Step-1

To a solution of 4-bromo-1-methyl-5-phenyl-1H-pyrazole (0.2 g) in drytoluene (5 ml), piperizene (0.36 g) and sodium tert-butoxide (0.12 g)were added and reaction mixture was degassed for 5 minute. Then, BINAP(0.05 g), Pd(dba)₂ and DMF (0.1 ml) were added to the above reactionmixture and again degassed with nitrogen for 5 minute. Reaction mixturewas allowed to reflux for over-night. The reaction mixture was filteredthrough a celite pad and washed with ethyl acetate (2×20 ml). Thevolatiles ware removed under reduced pressure. The resulting crudeproduct was purified by column chromatography using MeOH/CHCl₃ (2:8) aseluent to afford G-13-In as light yellow oil.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (m, 4H), 2.64 (m, 4H), 3.67 (s, 3H),7.30 (s, 1H), 7.36-7.53 (m, 5H).

¹³C NMR (CD₃OD): δ 30.77, 41.09, 46.34, 48.37, 52.90, 53.78, 54.09,129.88, 130.65, 131.21, 134.72, 135.53, 136.39, 163.08.

LCMS: 242.9 (M⁺+1).

Step-2

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (150 mg) in dry DMF (5 ml), G-13-In (96 mg), TBTU (175 mg) andDIPEA (0.2 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-13a asyellow color solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (t, 2H), 2.70 (t, 2H), 3.38 (bs, 2H),3.61 (t, 2H), 3.69 (s, 3H), 7.39 (s, 1H), 7.42-7.55 (m, 5H), 8.12 (s,1H), 8.31 (bs, 1H), 9.01 (s, 1H), 13.05 (bs, 1H).

LCMS: 500.2 (M⁺+1).

HPLC: 97.37% (0.1% TFA/ACN; Column: C18 BDS 4.6×50 mm).

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (150 mg) in dry DMF (5 ml), G-13-In (96 mg), TBTU (0.117 g) andDIPEA (0.2 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-13b asyellow color solid.

¹H NMR (400 MHz, CDCl₃): δ 2.56 (s, 3H), 2.84 (s, 1H), 2.93 (bs, 1H),3.50 (bs, 2H), 3.77 (bs, 4H), 4.09 (s, 3H), 7.27 (s, 1H), 7.37-7.48 (m,5H), 8.18 (s, 1H), 9.10 (s, 1H), 11.03 (s, 1H).

LCMS: 526.2 (M⁺+1).

HPLC: 94.59% (NH₄OAc/ACN; Column: C18 XDB, 4.6×250 mm).

Preparation of Compound G-14a and G-14b Preparation of IntermediateG-14-In

Step-1

A 100 ml three necked round bottom flask was charged with6-phenyl-5-(piperazin-1-yl)pyridazin-3(2H)-one (2.0 g), dry potassiumcarbonate (2.1 g) and dry DMF (150 ml) under nitrogen atmosphere. Thereaction mixture was stirred at room temperature and benzoylchloride(1.5 g) was added into the reaction mixture very slowly. The reactionmixture was heated 120° C. for 4 hrs. The progress of reaction wasmonitored by TLC. After consumption of starting material reactionmixture was cooled to 0° C., ice-cold water (20.0 ml) was added toreaction mixture and the organic compound was extracted intoethylacetate (4×20 ml). Combined organic layers were dried (Na₂SO₄) andconcentrated. The crude material was purified by column chromatographyusing MeOH/CHCl₃ (1:9) as eluent to afford5-(4-benzoylpiperazin-1-yl)-6-phenylpyridazin-3 (2H)-one.

¹H NMR (400 MHz, CDCl₃): δ 2.94-3.41 (bs, 4H), 3.49-3.73 (bs, 4H), 6.33(s, 1H), 7.27-7.68 (m, 10H), 11.5 (bs, 1H).

LCMS: 361.0 (M⁺+1).

Step-2

To 5-(4-benzoylpiperazin-1-yl)-6-phenylpyridazin-3(2H)-one (1.3 g) takenin single necked round bottom flask, phosphorusoxychloride (10 ml) wasadded and the mixture was heated to 80° C. for 4 hrs. Reaction mixturewas cooled to room temperature and concentrated to remove excessphosphorus oxychloride. Residue was slowly poured into ice andneutralized with solid sodium bicarbonate. The mixture was extractedwith Ethyl acetate (3×100 ml). The combined organic layer was dried overanhydrous sodium sulphate and concentrated to afford(4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone aswhite solid.

¹H NMR (400 MHz, CDCl₃): δ 2.96-3.09 (bs, 4H), 3.43-3.51 (bs, 2H), 3.80(bs, 2H), 6.94 (s, 1H), 7.26-7.84 (m, 10H).

LCMS: 378.8 (M⁺−1).

Step-3

To (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone(1 g) dissolved in methanol (40 ml), and dimethyl amine in THF (10 ml)was added under nitrogen atmosphere and the reaction mixture was heatedto 60° C. for 18 hrs. The progress of reaction was monitored by TLC.After consumption of starting material, reaction mixture was cooled toroom temperature and neutralized with solid sodium bicarbonate. Themixture was extracted with dichloromethane (3×10 ml). The combinedorganic layer was dried over anhydrous sodium sulphate and concentratedto afford(4-(6-(dimethylamino)-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanoneas yellow liquid.

LCMS: 387.9 (M⁺+1).

Step-4

To(4-(6-(dimethylamino)-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone(18 g) taken in round bottom flask, concentrated hydrochloric acid (10ml) was added. The reaction mixture was stirred at 85° C. for 6 hrs. Theprogress of reaction was monitored by TLC. After consumption of startingmaterial, reaction mixture was cooled to room temperature. Residue wasslowly poured into ice and neutralized with solid sodium bicarbonate.The mixture was extracted with dichloromethane (3×10 ml). The combinedorganic layer was dried over anhydrous sodium sulphate and concentratedto afford G-14-In as yellow liquid.

¹H NMR (400 MHz, CDCl₃): δ 2.46 (s, 6H), 2.96-3.13 (d, 4H), 3.14-3.49(d, 4H), 6.14 (s, 1H), 7.27-7.43 (m, 5H), 7.87 (s, 1H).

LCMS: 283.9 (M⁺+1).

Preparation of G-14a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-14-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-14aas yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.90 (t, 2H), 3.0 (t, 2H), 3.11 (s, 6H),3.31 (m, 2H), 3.31 (t, 2H), 6.38 (s, 1H), 7.36-7.47 (m, 5H), 8.12 (s,1H), 8.31 (t, 2H), 9.01 (s, 1H), 13.01 (bs, 1H).

LCMS: 541.1 (M⁺+1).

HPLC: 99.64% (0.1% TFA/ACN; Column: BDS C18, 4.6×50 mm).

Preparation of G-14b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-14-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-14bas yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H), 2.91 (t, 2H), 2.99 (t, 2H),3.12 (s, 6H), 3.35 (m, 2H), 3.58 (t, 2H), 3.99 (s, 3H), 6.40 (s, 1H),7.35-7.47 (m, 5H), 7.89 (s, 1H), 8.20 (s, 1H), 9.22 (s, 1H), 12.35 (bs,1H).

LCMS: 567.2 (M⁺+1).

HPLC: 99.82% (0.1% TFA/ACN; Column: BDS C18, 4.6×50 mm).

Preparation of G-15a and G-15b Preparation of Intermediate G-15-In

Step-1

To (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone(1 g) dissolved in methanol (40 ml), and palladium carbon (10 mol %) wasadded very slowly under nitrogen atmosphere and the reaction mixture wasstirred under hydrogen atmosphere (1 kg pressure) for 3 hrs. Theprogress of reaction was monitored by TLC. After consumption of startingmaterial, the reaction mixture was filtered through celite, washed withmethanol and the filterate was concentrated under reduced pressure toget phenyl(4-(3-phenylpyridazin-4-yl)piperazin-1-yl)methanone as whitesolid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.45-4.04 (bs, 8H), 7.40 (s, 1H), 7.42-7.95(m, 10H), 9.0 (s, 1H).

Step-2

To phenyl(4-(3-phenylpyridazin-4-yl)piperazin-1-yl)methanone (18 g)taken in round bottom flask, concentrated hydrochloric acid (10 ml) wasadded. The reaction mixture was stirred at 85° C. for 6 hrs. Theprogress of reaction was monitored by TLC. After consumption of startingmaterial, reaction mixture was cooled to room temperature. Residue wasslowly poured into ice and neutralized with solid sodium bicarbonate.The mixture was extracted with dichloromethane (3×10 ml). The combinedorganic layer was dried over anhydrous sodium sulphate and concentratedto afford G-15-In as yellow liquid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.64 (d, 4H), 2.80 (d, 4H), 4.09 (s, 1H),7.11 (s, 1H), 7.42-7.83 (m, 5H), 8.82 (s, 1H).

Preparation of G-15a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-15-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-15aas yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.94 (t, 2H), 3.07 (t, 2H), 3.39 (m, 2H),3.62 (t, 2H), 7.20 (s, 1H), 7.46-7.54 (m, 5H), 8.12 (s, 1H), 8.31 (d,2H), 8.88 (d, 1H), 9.01 (s, 1H), 13.01 (bs, 1H).

LCMS: 498.1 (M⁺+1).

HPLC: 99.41% (0.1% HCOOH/ACN; Column: Genesis C18, 4.6×50 mm).

Preparation of G-15b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-15-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using MeOH/CHCl₃ (1:9) as eluent to afford G-15bas yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H), 2.94 (t, 2H), 3.06 (t, 2H),3.33 (m, 2H), 3.58 (t, 2H), 3.98 (s, 3H), 7.23 (d, 1H), 7.46-7.54 (m,5H), 8.21 (s, 1H), 8.89 (d, 1H), 9.24 (s, 1H), 12.39 (bs, 1H).

LCMS: 524.1 (M⁺+1).

HPLC: 96.79% (0.1% HCOOH/ACN; Column: Genesis C18, 4.6×50 mm).

Preparation of Compound G-16

Step-1

Sodium hydride (0.1 g) was taken in dry DMF (2 ml) and a solution oftert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 gin 2 ml of DMF) was added slowly at 0° C. The reaction mixture wasstirred for 30 min at 0° C. and a solution of 2-chloroethylmorpholinehydrochloride (0.3 g) in DMF (1 ml) was added very slowly. The reactionmixture was allowed to stir over night at room temperature. The reactionmixture was quenched with cold water (5 ml) and extracted with ethylacetate (3×40 ml). Evaporation of solvent under reduced pressure gavecrude product, which, was purified by column chromatography using ethylacetate/hexane (2:8) as eluent to afford compound tert-butyl4-(1-(2-morpholinoethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylateas pure solid product.

¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 2.65-2.70 (m, 4H), 2.84 (t,2H), 3.3-3.54 (m, 4H) 3.63 (m, 6H), 3.76 (m, 4H), 7.27-7.43 (m, 5H),7.54 (s, 1H).

LC-MS: 441 (M⁺+1)

Step-2

To tert-butyl4-(1-(2-morpholinoethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate(1 g) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was added at0° C. The reaction mixture was allowed to reach at room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-16-In, which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 2.65-2.70 (m, 4H), 2.84 (t, 2H), 3.3-3.54 (m,4H) 3.53 (m, 6H), 3.66 (m, 4H), 7.27-7.43 (m, 5H), 7.54 (s, 1H).

LC-MS: 340 (M⁺+1)

Step-3

2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-16-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using methanol/chloroform (1:9) as eluent toafford G-16 as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.41 (m, 4H), 2.69-2.75 (m, 4H), 2.84 (s,2H), 3.53 (d, 6H, 4 Hz), 3.76 (s, 2H), 4.16 (t, 2H, J=8 Hz), 7.25 (t,1H, J=6 Hz), 7.38 (t, 2H, J=8 Hz), 7.66 (s, 1H), 7.96 (d, 2H, J=8 Hz),8.11 (s, 1H), 8.30 and 8.34 (2s, 2H), 9.02 (s, 1H), 13.12 (s, 1H).

LCMS: 599.2 (M⁺+1).

HPLC: 95.4% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Preparation of Compound G-17a and G-17b Preparation of IntermediateG-17-In

Step-1

To a stirred solution of methyl piperidine 4-carboxylate HCl salt (5 g)in dichloromethane, triethylamine was added until the solution is basic.To this basified reaction mixture, Boc-anhydride (7.2 g) was added andallowed to stir at room temperature for overnight. The reaction mixturewas quenched with water (20 ml) and extracted with dichloromethane (3×10ml). The combined organic layers was dried over Na₂SO₄ and concentratedto dryness to afford 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylateas a white color solid, which taken for the next reaction withoutfurther purification.

¹H NMR (400 MHz, CDCl₃): δ 1.45 (s, 9H), 1.62-1.64 (m, 2H), 1.89 (m,2H), 2.83 (m, 2H), 3.69 (s, 3H), 4.1 (m, 2H).

LC-MS: 244 (M⁺+1)

Step-2

To a stirred solution of phenyl ethylene diamine (3 g) taken in drytoluene (50 ml), cooled to −10° C., trimethylaluminium (36 ml, 2Msolution in hexane) was added drop wise for 30 minutes. The reactionmixture was brought to room temperature and was heated to 50° C.1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate (8 g) taken in drytoluene (50 ml) added to the above mixture in a drop wise fashion. Thecombined mixture was stirred at 110° C. for 5 hours, then allowed stirover night at room temperature. To the reaction mixture water (50 ml)was added followed by methanol (50 ml) and allowed to stir for 15minutes at 0° C. The whole mixture was then filtered through celite bedand washed with chloroform. The combined filtrate was concentrated underreduced pressure. The resulting crude was purified by columnchromatography using methanol/chloroform (2:8) as eluent to affordtert-butyl4-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)piperidine-1-carboxylate assolid product.

¹H NMR (400 MHz, CD₃OD): δ 1.47 (s, 9H), 1.57-1.60 (m, 2H), 1.72-1.76(m, 2H), 2.56-2.57 (m, 3H), 3.84 (m, 2H), 3.92 (m, 2H), 4.08 (m, 2H),7.27-7.48 (m, 5H).

LCMS: 230.1 (M⁺+1).

Step-3

To tert-butyl4-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)piperidine-1-carboxylate (500mg) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was added at 0°C. The reaction mixture was allowed to reach room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-17-In, which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, CD₃OD): δ 1.93 (m, 2H), 2.01 (m, 2H), 2.94 (m, 2H),3.33 (m, 2H), 3.42 (m, 2H), 4.11 (m, 2H), 4.36 (m, 1H), 7.51-7.62 (m,5H).

¹³C NMR (CD₃OD): δ 31.28, 35.85, 46.45, 49.45, 52.11, 54.67, 79.48,126.54, 127.54, 130.76, 142.57, 170.43.

LCMS: 231.0 (M⁺+1).

Preparation of G-17a

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), G-17-In (0.083 g), TBTU (0.128 g) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using methanol/chloroform (2:8) as eluent to afford G-17aas yellow color solid.

¹H NMR (DMSO-d₆): δ 1.5-1.9 (m, 4H), 2.73 (t, 2H), 3.01 (t, 1H), 3.58(d, 1H), 3.77 (t, 2H), 3.94 (t, 2H), 4.36 (d, 1H), 7.3 (m, 3H), 7.45 (m,2H), 8.0 (s, 1H), 8.06 (s, 1H), 9.03 (s, 1H).

LCMS: 487.1 (M⁺+1).

HPLC: 94.7% (0.1% HCOOH/ACN; Column: Genesis C18 50×4.6 mm, 3μ)

Preparation of G-17b

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), G-17-In (0.076 g), TBTU (0.117 g) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using methanol/chloroform (2:8) as eluent to afford G-17b(30 mg, 17%) as yellow color solid.

¹H NMR (DMSO-d₆): δ 1.65 (m, 4H), 2.49 (s, 3H), 2.80 (m, 2H), 3.01 (t,1H), 3.55 (t, 1H), 3.72 (m, 4H), 3.95 (s, 3H), 4.29 (d, 1H), 7.20 (m,3H), 7.40 (t, 2H), 7.83 (s, 1H), 8.15 (s, 1H), 9.24 (s, 1H).

LCMS: 513.2 (M⁺+1).

HPLC: 90.3% (0.1% TFA/CAN; Column: C18 BDS, 4.6×250 mm).

Preparation of Compound G-18 Preparation of Intermediate G-18-In

Step-1

To a stirred solution of tert-butyl4-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)piperidine-1-carboxylate (100mg) in dry benzene (5 ml), nickel peroxide (350 mg) dissolved in drybenzene (20 ml) was added. The reaction mixture was refluxed forover-night and filtered through a celite pad using CHCl₃ as eluent. Thecombined organic layer was removed under reduced pressure. The resultingoil was purified by column chromatography using ethyl acetate\hexane(3:7) to afford tert-butyl4-(1-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate as pure product

¹H NMR (400 MHz, CD₃OD): δ 1.47 (s, 9H), 1.67-1.70 (m, 2H), 1.72-1.76(m, 2H), 2.56-2.57 (m, 1H), 3.3 (m, 2H), 3.5 (m, 2H), 7.0-7.2 (S, 2H),7.27-7.48 (m, 5H).

LC-MS: 328.1 (M⁺+1).

Step-2

To tert-butyl 4-(1-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate (500mg) taken in dry dichloromethane (10 ml), TFA (5 ml) was added at 0° C.The reaction mixture was allowed reach at room temperature and stirredfor over-night. The volatiles were removed using reduced pressure andthe residue was diluted with dichloromethane (10 ml). The organic layerwas washed with saturated NaHCO₃ (2×10 ml), brine (20 ml) and was driedover Na₂SO₄. Evaporation of solvent gave desire amine G-18-In, which wastaken for the next reaction without further purification.

¹H NMR (400 MHz, CD₃OD): δ 1.76-1.82 (m, 2H), 2.56 (m, 2H), 2.76-2.80(m, 1H), 3.05 (m, 2H), 3.5 (m, 2H), 7.0-7.15 (S, 2H), 7.37-7.48 (m, 5H).

LCMS: 228.1 (M⁺+1).

Preparation of G-18a

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), G-18-In (0.076 g), TBTU (0.117 g) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using methanol/chloroform (1:9) as eluent to afford G-18aas yellow color solid.

¹H NMR (DMSO-d₆): δ 1.8 (m, 4H), 3.0 (m, 3H), 3.62 (d, 1H), 4.36 (d,1H), 6.97 (s, 1H), 7.24 (s, 1H), 7.43 (d, 2H), 7.55 (m, 3H), 8.12 (s,1H), 8.25 (s, 1H), 8.31 (s, 1H), 9.02 (s, 1H), 13.06 (bs, 1H).

LCMS: 485.1 (M⁺+1).

HPLC: 97.3% (0.1% TFA/ACN; Column: C18 BDS, 4.6×50 mm).

Preparation of G-18b

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 ml), G-18-In (0.076 g), TBTU (0.117 g) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at r.t. forover night. The reaction was quenched with methanol (10 ml) and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃ and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated usingrotary evaporator. The resulting crude was purified by columnchromatography using methanol/chloroform (1:9) as eluent to afford G-18bas yellow color solid.

¹H NMR (CD₃OD): δ 1.9 (m, 4H), 2.56 (s, 3H), 2.85 (m, 1H), 3.12 (m, 2H),3.8 (d, 1H), 4.04 (s, 3H), 4.59 (d, 1H), 7.05 (s, 1H), 7.16 (s, 1H),7.43 (s, 2H), 7.56 (m, 3H), 7.84 (s, 1H), 8.27 (s, 1H), 9.23 (s, 1H).

¹³C NMR (CD₃OD): δ 13.76, 31.63, 32.18, 34.95, 42.24, 47.52, 57.55,115.88, 122.15, 122.71, 124.57, 125.39, 127.52 (2C), 127.94, 130.25,130.98 (2C), 131.65, 138.62, 139.54, 142.83, 151.21, 151.64, 162.93,168.43, 187.37.

LCMS: 511.2 (M⁺+1).

HPLC: 97.3% (0.1% TFA/ACN; Column C18, BDS 4.6×50 mm).

Preparation of G-19a and G-19b Preparation of Intermediate G-19-In

Step-1

To a stirred solution of formamidine acetate (2.8 g) in triethylamine (6ml) in a sealed tube, was added tert-butyl4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate(1.0 g) and the reaction mixture was heated at 140° C. for 6 h. Thereaction mixture was brought to room temperature and triethylamine wasremoved under reduced pressure. Water (10 ml) was added to the residueand the organic compound was extracted into ethylacetate (4×20 ml).Combined organic layers were dried (Na₂SO₄) and concentrated. The crudematerial was purified by column chromatography using methanol/chloroform(1:9) to give tert-butyl4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate.

¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 2.59 (s, 4H), 3.52-3.54 (s,4H), 7.27-7.50 (m, 5H), 8.41 (s, 1H), 8.97 (s, 1H).

LC-MS: 341 (M⁺+1)

Step-2

To tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate (1 g)dissolved in dry dichloromethane (10 ml), TFA (5 ml) was added at 0° C.The reaction mixture was allowed to reach room temperature and stirredfor over-night. The volatiles were completely removed and resultingresidue was diluted with dichloromethane (20 ml). The organic layer waswashed with saturated NaHCO₃ (2×10 ml), brine, dried over Na₂SO₄.Evaporation of solvent gave desire amine G-19-In (0.5 g), which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 2.59 (s, 4H), 3.52-3.54 (s, 4H), 7.27-7.50(m, 5H), 8.41 (s, 1H), 8.97 (s, 1H).

LC-MS: 240 (M⁺+1)

Preparation of G-19a

2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-19-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using methanol/chloroform (1:9) as eluent toafford G-19a as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.92 (bs, 2H), 3.02 (bs, 2H), 3.45 (bs,2H), 3.67 (bs, 2H), 7.47-7.53 (m, 3H), 8.09-8.12 (m, 3H), 8.33 (m, 2H),8.56 (s, 1H), 8.89 (s, 1H), 9.01 (s, 1H), 13.06 (bs, 1H).

¹³C NMR (400 MHz, DMSO-d₆): δ 14.13, 41.03, 45.63, 50.77, 51.15, 56.97,94.80, 115.74, 121.38, 123.13, 124.15, 127.22, 129.11, 129.70, 136.51,139.74, 139.90, 141.28, 149.63, 150.74, 162.12, 166.39, 185.36.

LCMS: 498.1 (M⁺+1).

HPLC: 96.67% (0.1% TFA/ACN; Column: Hypersil, BDS C18, 4.6×50 mm).

Preparation of G-19b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), G-19-In (0.076 g), TBTU (0.116 g) and Hunig's base (0.1ml) were combined in dry DMF (4 ml). The reaction mixture was stirred atroom temperature for over night. The mixture was quenched with methanol(10 ml) and volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml), washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude was purified bycolumn chromatography using methanol/chloroform (1:9) as eluent toafford G-19b as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.57 (s, 3H), 3.03 (t, 2H), 3.12 (t, 2H),3.57 (t, 2H), 3.82 (t, 2H), 4.08 (s, 3H), 7.27-7.51 (m, 5H), 7.78 (s,1H), 8.22 (s, 1H), 8.45 (s, 1H), 9.00 (s, 1H), 9.12 (s, 1H), 11.05 (bs,1H).

LCMS: 524.1 (M⁺+1).

HPLC: 98.38% (0.1% TFA in H₂O/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Preparation of Compound 20

Step-1

Sodium hydride (0.1 g) was taken in dry DMF (2 ml) and a solution oftert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 gin 2 ml of DMF) was added slowly at 0° C. The reaction mixture wasstirred for 30 min at 0° C. and a solution of ethylbromoacetate (1 g) inDMF (1 ml) was added very slowly. The reaction mixture was allowed tostir over night at room temperature. The reaction mixture was quenchedwith cold water (5 ml) and extracted with ethyl acetate (3×40 ml).Evaporation of solvent under reduced pressure gave crude product, which,was purified by column chromatography using ethyl acetate/hexane (2:8)as eluent to afford tert-butyl4-(1-(2-ethoxy-2-oxoethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylatebas pure solid product.

¹H NMR (400 MHz, CDCl₃): δ 1.2 (t, 3H), 1.48 (s, 9H), 2.86 (m, 4H), 3.54(m, 4H), 4.08 (t, 2H), 5.0 (s, 2H), 7.28-7.43 (m, 5H), 7.8 (s, 1H).

LC-MS: 415 (M⁺+1)

Step-2

To tert-butyl4-(1-(2-ethoxy-2-oxoethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate(1 g) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was added at0° C. The reaction mixture was allowed to reach at room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-20-In, which was usedfor the next reaction without further purification.

Step-3

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.1 g), amine G-20-In (0.08 g), TBTU (0.12 g) and Hunig's base(0.15 ml) were combined in dry DMF (5 ml). The reaction mixture wasstirred at room temperature for over night. The mixture was quenchedwith methanol (10 ml) and volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml), washed with10% NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting crude waspurified by column chromatography using 5% methanol/chloroform (1:9) aseluent to afford G-20.

¹H NMR (400 MHz, CDCl₃): δ 1.2 (t, 3H), 2.75 (t, 2H), 2.86 (t, 2H), 3.54(t, 2H), 3.77 (t, 2H), 4.18 (t, 2H), 5.0 (s, 2H), 7.28 (m, 1H), 7.3 (m,2H), 7.6 (S, 1H), 7.95 (d, 2H), 8.1 (s, 1H), 8.35 (d, 2H), 9.0 (s, 1H),13 (s, 1H).

LC-MS: 572 (M⁺+1).

HPLC: 95.166% (0.1% TFA/ACN; Column: HypersilBDSC18 5 u (4.6×50) mm).

Preparation of Compound G-21

Step-1

Sodium hydride (0.1 g) was taken in dry DMF (2 ml) and a solution oftert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 gin 2 ml of DMF) was added slowly at 0° C. The reaction mixture wasstirred for 30 min at 0° C. and a solution of chloroacetonitrile (0.138g) in DMF (1 ml) was added very slowly. The reaction mixture was allowedto stir over night at room temperature. The reaction mixture wasquenched with cold water (5 ml) and extracted with ethyl acetate (3×40ml). Evaporation of solvent under reduced pressure gave crude product,which, was purified by column chromatography using ethyl acetate\hexane(2:8) as eluent to afford tert-butyl4-(1-(cyanomethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate aspure solid product.

¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 2.90 (s, 4H), 3.53-3.55 (s,4H), 5.05 (s, 2H), 7.26-7.44 (m, 5H), 7.99 (s, 1H).

LC-MS: 367 (M⁺+1).

Step-2

To tert-butyl4-(1-(cyanomethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (1g) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was added at 0°C. The reaction mixture was allowed to reach at room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-21-In, which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 2.90 (s, 4H), 3.53-3.55 (s, 4H), 5.05 (s,2H), 7.26-7.44 (m, 5H), 7.99 (s, 1H).

LC-MS: 367 (M⁺+1).

Step-3

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.098 g), compound G-21-In (0.076 g), TBTU (0.116 g) and Hunig'sbase (0.1 ml) were combined in dry DMF (4 ml). The reaction mixture wasstirred at room temperature for over night. The mixture was quenchedwith methanol (10 ml) and volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml), washed with10% NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting crude waspurified by column chromatography using methanol/chloroform (1:9) aseluent to afford G-21 as off white solid.

¹H NMR (400 MHz, CDCl₃): δ 2.6 (s, 3H), 2.9-3.2 (d, 4H), 3.63 (s, 2H),3.9 (s, 2H), 4.1 (s, 3H), 5.06 (s, 2H), 7.31-7.45 (m, 4H), 7.79 (s, 1H),7.95 (d, 2H), 8.23 (s, 1H), 9.15 (s, 1H), 11.02 (s, 1H).

LCMS: 551.1 (M⁺+1).

HPLC: 95.7% (0.1% TFA/ACN; Column: Hypersil BDS C18, 4.6×50 mm).

Preparation of Compound G-22a and G-22b Preparation of IntermediateG-22-In

Step-1

1,2,3-Triazole (5 g), 2-bromo pyridine (8.5 ml) and copper iodide (0.68g) was taken in dry DMF under Nitrogen atmosphere.1,2-(N,N-dimethyl)cyclohexyl diamine (1.02 g) and potassium phosphate(30.73 g) was added into above mixture. The reaction mixture was refluxat 110° C. for over night. TLC was checked no starting material and thereaction mixture was filtered through celite. The filtrate was dilutedwith water and product was extracted with dichloromethane. The organiclayer was evaporated and the crude product was purified by columnchromatography using 60-120 silica gel and pet ether\ethyl acetate aseluent to give compound 2-(1H-1,2,3-triazol-1-yl)pyridine as whitesolid.

¹H NMR (400 MHz, CDCl₃): δ 7.47 (m, 1H), 8.0 (s, 1H), 8.13 (d, 2H), 8.6(d, 2H), 8.84 (s, 1H).

LC-MS: 147 (M⁺+1)

Step-2

In a 100 ml 3 necked round bottom flask,2-(1H-1,2,3-triazol-1-yl)pyridine (2 g) was taken in dry THF (2 ml)under nitrogen. n-Butyl lithium (2.3 ml) was added at −78° C. andstirred for 5 minutes, then bromine (1.86 ml was added dropwise to theabove reaction mixture. Reaction mixture was stirred at −78° C. for 1hour. TLC was checked no starting material and the reaction mixture wasquenched with saturated ammonium chloride (50 ml) and ethyl acetate wasadded. The organic layer was washed with sodium bisulphate, brine, driedand concentrated. The crude product was purified by columnchromatography using pet ether & ethyl acetate as eluent to givecompound 2-(5-bromo-1H-1,2,3-triazol-1-yl)pyridine as yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 7.68 (m, 1H), 7.86 (m, 1H), 8.1 (s, 1H), 8.15(m, 1H), 8.7 (m, 1H).

LC-MS: 226 (M⁺+1).

Step-3

In a 100 ml single neck round bottom flask,2-(5-bromo-1H-1,2,3-triazol-1-yl)pyridine (1.5 g), piperazine (2.8 g)and sodium tert-butoxide (0.56 g) was taken in dry toluene (20 ml) anddegasified for 20 min. Then Pd(dba)₂ (0.3 g), BiNAP (0.41 g) was addedand again degasified for 10 min. The reaction mixture was reflux at 107°C. for over night. TLC was checked no starting material. Reactionmixture was diluted with 25 ml of water and extracted withdichloromethane. The organic layer was separated and concentrated. Thecrude product was purified by column chromatography using 60-120 silicagel and 6% methanol\chloroform as eluent to give compound G-22-In aswhite solid.

¹H NMR (400 MHz, CDCl₃): δ 2.6-2.87 (d, 8H), 7.41 (s, 1H), 7.5-7.6 (m,1H), 7.73 (d, 1H), 8.0 (m, 1H), 8.64 (d, 1H).

LC-MS: 231 (M⁺+1).

Preparation of G-22a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.119 g), compound G-22-In (0.1 g), BOP reagent (0.19 g) andHunig's base (0.22 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography using methanol\chloroform(1:9) as eluent to afford G-22a as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.96-2.98 (t, 2H), 3.11 (t, 2H), 3.37-3.46(t, 2H), 3.68-3.71 (t, 2H), 7.52 (s, 1H), 7.58 (d, 1H), 7.8 (d, 1H), 8.1(t, 2H), 8.31-8.36 (d, 2H), 8.65 (t, 1H), 9.0 (s, 1H), 13 (s, 1H).

LC-MS: 487 (M⁺+1).

HPLC: 84.9% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of G-22b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.12 g), compound G-22-In (0.1 g), BOP reagent (0.19 g) andHunig's base (0.22 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography using methanol\chloroform(1:9) as eluent to afford G-22b as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (s, 3H), 2.96-2.98 (t, 2H), 3.11 (t,2H), 3.37-3.46 (t, 2H), 3.68-3.71 (t, 2H), 4.0 (s, 1H), 7.52 (s, 1H),7.58 (m, 1H), 7.8 (d, 1H), 7.88 (s, 1H) 8.1 (t, 1H), 8.31-8.36 (d, 1H),8.65 (d, 1H), 9.23 (s, 1H).

LC-MS: 513 (M⁺+1).

HPLC: 96.9% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of Compound G-23

Step-1

Sodium hydride (0.02 g) was taken in dry DMF (5 ml) and a solution oftert-butyl 4-(5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate(0.015 g in 5 ml of DMF) was added slowly at 0° C. The reaction mixturewas stirred for 30 min at 0° C. and methyl iodide (0.13 g) was addedvery slowly. The reaction mixture was allowed to stir over night at roomtemperature. The reaction mixture was quenched with cold water (5 ml)and extracted with ethyl acetate (3×40 ml). Evaporation of solvent underreduced pressure gave crude product, which, was purified by columnchromatography using 60-120 silica gel methanol\dichloromethane (1:9) aseluent to afford tert-butyl4-(2-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate.

¹H NMR (400 MHz, DMSO-d₆): δ 1.4 (s, 9H), 2.92 (d, 4H), 3.43 (m, 5H),4.05 (m, 2H), 7.33 (m, 1H), 7.45 (t, 2H), 7.85 (d, 2H).

LCMS: 345.1 (M⁺+1).

Step-2

To tert-butyl4-(2-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate.(500 mg) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was addedat 0° C. The reaction mixture was allowed to reach room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-23-In, which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 2.92 (d, 4H), 3.23 (m, 5H), 4.05 (m, 2H),7.33 (m, 1H), 7.45 (t, 2H), 7.85 (d, 2H).

LCMS: 245.1 (M⁺+1).

Step-3

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg\) in dry DMF (5 ml), G-23-In (0.076 g), TBTU (0.117 g) andDIPEA (0.1 ml) were added. The reaction mixture was stirred at roomtemperature for over night. The reaction was quenched with methanol (10ml) and the volatiles were removed under reduced pressure. The resultingoil was diluted with ethyl acetate (50 ml) and washed with 10% NaHCO₃and brine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated using rotary evaporator. The resulting crude was purifiedby column chromatography using methanol\dichloromethane (2:8) as eluentto afford G-23 as an amorphous solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (s, 3H), 2.98-3.0 (t, 2H), 3.0-3.10 (t,2H), 3.5-3.53 (t, 2H), 3.73-3.79 (t, 2H), 4.01 (s, 3H), 4.07 (s, 3H),7.33 (m, 1H), 7.45 (t, 2H), 7.85 (d, 2H), 7.9 (s, 1H), 8.23 (s, 1H),9.25 (s, 1H), 12.42 (s, 1H).

LCMS: 527 (M⁺+1).

HPLC: 95% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of Compound G-24a and G-24b Preparation of IntermediateG-24-In

Step-1

To a stirred solution of N-Boc piperazine (5 g) in dry dichloromethane(100 ml), triethyl amine (10 ml) followed by chloro acetonitrile (25.02ml) were added dropwise. The reaction mixture was allowed to stir atroom temperature for overnight. The solvent was removed under vacuum andresidue was diluted with dichloromethane (200 ml). The organic layer waswashed with water, brine and concentrated to dryness under reducedpressure to afford tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate,which was used for the next reaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 1.47 (s, 9H), 2.55 (t, 4H), 3.49 (t, 4H),3.55 (s, 2H).

GC MS: 225

Step-2

In a 100 ml 3 necked round bottom flask, intermediate tert-butyl4-(cyanomethyl)piperazine-1-carboxylate (7 g) was taken in dry THF (125ml) under nitrogen. lithium bis trimethylsilyl amide (10.8 g) was addeddropwise at −78° C. and stirred for 1 hr, then diethyl chloro phosphate(5.84 g) in 5 ml dry THF was added drop wise to the above reactionmixture. Reaction mixture was stirred at −78° C. for 1 hour. TLC waschecked no starting material and the reaction mixture was quenched withsaturated ammonium chloride (250 ml) and ethyl acetate was added. Theorganic layer was washed with brine, dried and concentrated. The crudeproduct was purified by column chromatography using 230-400 silica gel2.5% methanol\chloroform as eluent to give compound tert-butyl4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate as yellowliquid.

¹H NMR (400 MHz, CDCl₃): δ 1.37 (t, 6H), 1.47 (s, 9H), 2.55 (t, 2H), 3.0(t, 2H), 3.55 (m, 4H), 3.87-3.93 (d, 1H), 4.3 (q, 4H).

LCMS: 262 (M⁺−101).

Step-3

In a 100 ml 3 necked round bottom flask, intermediate tert-butyl4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate (5.5 g) wastaken in dry THF (25 ml) under nitrogen. Sodium bis trimethylsilyl amide(3.3 g) was added dropwise at 0° C. and stirred for 30 min, thenpyridine-2-carboxaldehyde (1.67 g) in 15 ml dry THF was added dropwiseto the above reaction mixture at 0° C. Reaction mixture was stirred atroom temperature for overnight. TLC was checked no starting material andthe reaction mixture was quenched with saturated ammonium chloride (50ml) and ethyl acetate was added. The organic layer was washed withbrine, dried and concentrated to get crude product compound tert-butyl4-(1-cyano-2-(pyridin-2-yl)vinyl)piperazine-1-carboxylate as yellowliquid.

¹H NMR (400 MHz, CDCl₃): δ 1.47 (s, 9H), 3.10-3.2 (t, 4H), 3.55 (t, 4H),6.24 (s, 1H), 7.14 (m, 1H), 7.55-7.67 (m, 2H), 8.58-8.6 (d, 1H).

LCMS: 315 (M⁺+1).

Step-4

To a stirred solution of tert-butyl4-(1-cyano-2-(pyridin-2-yl)vinyl)piperazine-1-carboxylate (2.5 g),sodium azide (0.4 g) were taken in dry DMSO (4 ml) and heated to 110° C.overnight. The reaction mixture was carefully quenched with water (10ml) and the reaction mixture was extracted with dichloromethane (3×10ml). The combined organic layer was washed with brine (10 ml), driedover sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by column chromatography usingmethanol:chloroform (1:9) as an eluent to afford tert-butyl4-(5-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate aswhite solid.

¹H NMR (400 MHz, CDCl₃): δ 1.49 (s, 9H), 3.17-3.2 (t, 4H), 3.65 (t, 4H),7.44 (m, 1H), 8.0 (m, 1H), 8.1 (d, 1H), 8.88 (d, 1H).

LCMS: 331 (M⁺+1).

Step-5

To tert-butyl4-(5-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate (500mg) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was added at 0°C. The reaction mixture was allowed to reach room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-24-In, which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 3.17-3.2 (t, 4H), 3.45 (t, 4H), 7.44 (m,1H), 8.0 (d, 2H), 8.65 (d, 1H), 8.88 (bs, 1H).

LCMS: 231 (M⁺+1).

Preparation of G-24a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (95 mg), compound G-24-In (100 mg), BOP reagent (0.16 mg) andHunig's base (0.2 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography usingdichloromethane\methanol (1:9) as eluent to afford G-24a as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.17-3.2 (t, 4H), 3.55 (t, 2H), 3.8 (t,2H), 7.44 (m, 1H), 7.9-8.0 (m, 2H), 8.15 (s, 1H), 8.33-8.36 (d, 2H), 8.5(m, 1H), 9 (s, 1H), 13 (bs, 1H), 14.48 (s, 1H).

LCMS: 488.8 (M⁺+1).

HPLC: 90.4% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of G-24b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (95 mg), compound G-24-In (100 mg), BOP reagent (0.16 mg) andHunig's base (0.2 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography usingdichloromethane\methanol (1:9) as eluent to afford G-24b as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.55 (s, 3H), 3.17-3.2 (t, 4H), 3.55 (t,2H), 3.8 (t, 2H), 4 (s, 3H), 7.31 (m, 1H), 7.9-8.0 (m, 3H), 8.25 (s,1H), 8.63 (d, 1H), 9.24 (s, 1H), 12.4 (bs, 1H), 14.48 (s, 1H).

LCMS: 512.8 (M⁺+1).

HPLC: 98.0% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of Compound G-25a and G-25b Preparation of IntermediateG-25-In

Step-1

In a 100 ml 3 necked round bottle flask, tert-butyl4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate (5.0 g) wastaken in dry THF (25 ml) under nitrogen. Sodium bis trimethylsilyl amide(3.0 g) was added drop wise at 0° C. and stirred for 30 min, thenthiazole-2-carboxaldehyde (1.60 g) in 15 ml dry THF was added drop wiseto the above reaction mixture at 0° C. Reaction mixture was stirred atroom temperature for overnight. TLC was checked no starting material andthe reaction mixture was quenched with saturated ammonium chloride (50ml) and ethyl acetate was added. The organic layer was washed withbrine, dried and concentrated to get crude product tert-butyl4-(1-cyano-2-(thiazol-2-yl)vinyl)piperazine-1-carboxylate as yellowliquid.

¹H NMR (400 MHz, CDCl₃): δ 1.49 (s, 9H), 3.33 (t, 4H), 3.55 (m, 4H), 6.8(s, 1H), 7.31 (s, 1H), 7.82 (s, 1H).

LCMS: 321 (M⁺+1).

Step-2

To a stirred solution of tert-butyl4-(1-cyano-2-(thiazol-2-yl)vinyl)piperazine-1-carboxylate (2.25 g),sodium azide (0.4 g) were taken in dry DMSO (4 ml) and heated to 110° C.overnight. The reaction mixture was carefully quenched with water (10ml) and the reaction mixture was extracted with dichloromethane (3×10ml). The combined organic layer was washed with brine (10 ml), driedover sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by column chromatography usingmethanol:chloroform (1:9) as an eluent to afford tert-butyl4-(5-(thiazol-2-yl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate aswhite solid.

¹H NMR (400 MHz, CDCl₃): δ 1.55 (s, 9H), 3.33 (t, 4H), 3.68 (m, 4H),7.45 (s, 1H), 7.98 (s, 1H).

LCMS: 335.7 (M⁺+1).

Step-5

To tert-butyl4-(5-(thiazol-2-yl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate (500mg) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was added at 0°C. The reaction mixture was allowed to reach room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-25-In, which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 3.33 (t, 4H), 3.68 (m, 4H), 7.45 (s, 1H),7.98 (s, 1H). LCMS: 237 (M⁺+1).

Preparation of G-25a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (95 mg), compound G-25-In (100 mg), BOP reagent (0.16 mg) andHunig's base (0.2 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography usingdichloromethane\methanol (1:9) as eluent to afford G-25a as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.47-3.56 (dd, 6H), 3.8 (t, 2H), 7.7-7.9(s, 2H), 8.15 (s, 1H), 8.33-8.36 (d, 2H), 9 (s, 1H), 13 (bs, 1H), 14.7(s, 1H).

LCMS: 492 (M⁺−1).

HPLC: 86.6% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of G-25b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (95 mg), compound G-25-In (100 mg), BOP reagent (0.16 mg) andHunig's base (0.2 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography usingdichloromethane\methanol (1:9) as eluent to afford G-25b as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (s, 3H), 3.37-3.46 (m, 2H), 3.5 (m,4H), 3.8 (t, 2H), 3.99 (s, 3H), 7.7 (s, 1H), 7.9 (s, 2H), 8.25 (s, 1H),9.24 (s, 1H), 12.4 (bs, 1H), 14.7 (s, 1H).

LCMS: 518.6 (M⁺−1).

HPLC: 91.2% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of Compound G-26a and G-26b Preparation of IntermediateG-26-In

Step-1

To a stirred solution of phenyl hydrazine (3 g) in absolute alcohol (30ml) added dimethyl-N-cyanodithiocarbonate (4 g) slowly under nitrogenatmosphere. The reaction mixture was stirred at 80° C. for two hours.The progress of reaction was monitored by TLC. After consumption ofstarting material, the volatiles were removed under reduced pressurefrom the reaction mixture. The resulting residue was recrystallized frompet ether to afford 3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-amine asyellow solid. The solid obtained was taken to next step without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H), 6.54 (s, 2H), 7.33-7.53 (m,5H).

LCMS: 206.7 (M⁺+1).

Step-2

Sodium hydride (4.7 g) was taken in dry DMF (100 ml) and a solution ofcompound 3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-amine (4 g in 10 mlof DMF) was added slowly at 0° C. The reaction mixture was stirred for30 min at 0° C. and a solution of bis(2-chloroethyl)amine hydrochloride(4.15 g) in dry DMF (20 ml) was added very slowly. The reaction mixturewas allowed to stir over night at room temperature. The reaction mixturewas quenched with cold water (5 ml) and extracted with ethyl acetate(3×40 ml). Evaporation of solvent under reduced pressure gave crudeproduct, which, was purified by column chromatography usingmethanol\dichloromethane (1:9) as eluent to afford1-(3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine, G-26-In, asbrown oil.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H), 2.54-2.72 (m, 4H), 2.82-3.37(m, 4H), 7.38-7.60 (m, 5H).

LCMS: 275.9 (M⁺+1).

Preparation of G-26a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.1 g), amine G-26-In (0.09 g), TBTU (0.128 g) and Hunig's base(0.15 ml) were combined in dry DMF (5 ml). The reaction mixture wasstirred at room temperature for over night. The mixture was quenchedwith methanol (10 ml) and volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml), washed with10% NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting crude waspurified by column chromatography using methanol\dichloromethane (1:9)as eluent to afford G-26a.

¹H NMR (400 MHz, DMSO-d₆): δ 2.54 (s, 3H), 3.0 (m, 2H), 3.08 (m, 2H),3.38 (m, 2H), 3.69 (m, 2H), 7.38-7.66 (m, 5H), 8.12 (s, 1H), 8.31 (d,2H), 9.01 (s, 1H).

LCMS: 532.9 (M⁺+1).

HPLC: 97.66% (0.1% TFA/ACN; Column: C18 BDS, 250×4.6 mm).

Preparation of G-26b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.1 g), amine G-26-In (0.09 g), TBTU (0.11 g) and Hunig's base(0.15 ml) were combined in dry DMF (5 ml). The reaction mixture wasstirred at room temperature for over night. The mixture was quenchedwith methanol (10 ml) and volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml), washed with10% NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting crude waspurified by column chromatography using methanol\dichloromethane (1:9)as eluent to afford G-26b.

¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (s, 3H), 2.50 (s, 3H), 3.08 (m, 2H),3.20 (m, 2H), 3.42 (m, 2H), 3.67 (m, 2H), 3.98 (s, 3H), 7.39-7.67 (m,5H), 7.88 (s, 1H), 8.22 (s, 1H), 9.23 (s, 1H).

LCMS: 559.0 (M⁺+1).

HPLC: 99.71% (0.1% TFA/ACN; Column: C18 BDS, 50×4.6 mm).

Preparation of Compound G-27a and G-27b Preparation of IntermediateG-27-In

To a stirred solution of Raney nickel (2 g) in dry THF (10 ml) addedcompound 1-(3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine (1g) in dry THF (10 ml) slowly under nitrogen atmosphere. The reactionmixture was refluxed at 70° C. for three hours. The progress of reactionwas monitored by TLC. After consumption of starting material, thecatalysts were removed by filtration with the help of methanol (10×2ml). The filterate was concentrated to remove the volatiles. Theresulting crude product was purified by column chromatographymethanol\dichloromethane (1:9) as eluent to afford G-27-In as colorlessliquid.

¹H NMR (400 MHz, CD₃OD): δ 2.84-2.87 (t, 4H), 3.11-3.13 (t, 4H),7.45-7.79 (m, 5H), 7.92 (s, 1H).

LCMS: 229.9 (M⁺+1).

Preparation of G-27a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.1 g), amine G-27-In (0.08 g), TBTU (0.12 g) and Hunig's base(0.15 ml) were combined in dry DMF (5 ml). The reaction mixture wasstirred at room temperature for over night. The mixture was quenchedwith methanol (10 ml) and volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml), washed with10% NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting crude waspurified by column chromatography using methanol\dichloromethane (1:9)as eluent to afford G-27a.

¹H NMR (400 MHz, DMSO-d₆): δ 3.07 (m, 2H), 3.20 (m, 2H), 3.48 (m, 2H),3.71 (m, 2H), 7.40-7.83 (m, 5H), 8.12 (s, 1H), 8.31 (s, 2H), 8.35 (s,1H), 9.01 (s, 1H), 13.01 (bs, 1H).

LCMS: 487.1 (M⁺+1).

HPLC: 94.16% (0.1% TFA/ACN; Column: C18 BDS, 250×4.6 mm).

Preparation of G-27b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (0.1 g), amine G-27-In (0.076 g), TBTU (0.11 g) and Hunig's base(0.15 ml) were combined in dry DMF (5 ml). The reaction mixture wasstirred at room temperature for over night. The mixture was quenchedwith methanol (10 ml) and volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml), washed with10% NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting crude waspurified by column chromatography using methanol\dichloromethane (1:9)as eluent to afford G-27b.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H), 3.09 (m, 2H), 3.20 (m, 2H),3.43 (m, 2H), 3.67 (m, 2H), 3.98 (s, 3H), 7.40-7.57 (m, 5H), 7.84 (s,1H), 7.88 (s, 1H), 8.22 (s, 1H), 9.24 (s, 1H), 12.39 (bs, 1H).

LCMS: 513.1 (M⁺+1).

HPLC: 99.01% (0.1% TFA/ACN; Column: C18 BDS, 250×4.6 mm).

Preparation of Compound G-28a and G-28b Preparation of IntermediateG-28-In

Step-1

To a stirred solution of G-26-In (5 g) in dichloromethane (10 ml),triethylamine (7.6 ml) was added until the solution is basic. To thisbasified reaction mixture, Boc-anhydride (4.8 g) was added and allowedto stir at room temperature for overnight. The reaction mixture wasquenched with water (20 ml) and extracted with dichloromethane (3×10ml). The combined organic layers was dried over Na₂SO₄ and concentratedto dryness to afford tert-butyl4-(3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate(6 g) as a white color solid, which taken for the next reaction withoutfurther purification.

¹H NMR (400 MHz, DMSO-d₆): δ 1.49 (s, 9H), 2.50 (s, 3H), 2.54-2.72 (m,4H), 2.82-3.37 (m, 4H), 7.38-7.60 (m, 5H).

LC-MS: 378 (M⁺+1).

Step-2

To a stirred solution of tert-butyl4-(3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate(3 g) in dichloromethane (25 ml), m-chloro per benzoic acid (5.5 g) wasadded and allowed to stir at room temperature for overnight. Thereaction mixture was filtered through celite and celite pad was washedwith chloroform (3×10 ml). The combined organic layers were washed withsaturated sodium bicarbonate solution, brine and concentrated to drynessto get crude tert-butyl4-(3-(methylsulfonyl)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate.This was taken for column chromatography using 60-120 silica gel and1.0% methanol\chloroform as eluent to get pure compound tert-butyl4-(3-(methylsulfonyl)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylateas white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.49 (s, 9H), 3.1 (t, 4H), 3.31-3.36 (m,7H), 7.38-7.60 (m, 5H).

LC-MS: 411 (M⁺+1).

Step-3

To tert-butyl4-(3-(methylsulfonyl)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate(500 mg) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was addedat 0° C. The reaction mixture was allowed to reach room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-28-In, which was usedfor the next reaction without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 3.1 (t, 4H), 3.31-3.36 (m, 4H), 3.4-3.5 (s,3H), 7.38-7.60 (m, 5H).

LC-MS: 310 (M⁺+1).

Preparation of G-28a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (60 mg), compound G-28-In (80 mg), BOP reagent (0.1 g) and Hunig'sbase (0.2 ml) were combined in dry DMF (4 ml). The reaction mixture wasstirred at room temperature for over night. The mixture was quenchedwith methanol (10 ml) and volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml), washed with10% NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting crude waspurified by column chromatography using dichloromethane\methanol (1:9)as eluent to afford G-28a as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.15 (t, 2H), 3.28 (t, 2H), 3.3 (s, 3H),3.48 (t, 2H), 3.69 (t, 2H), 7.5 (m, 1H), 7.53 (m, 2H), 7.71 (d, 2H),8.12 (s, 1H), 8.31 (s, 1H), 8.36 (s, 1H), 9.01 (s, 1H), 13.07 (s, 1H).

LC-MS: 565 (M⁺+1).

HPLC: 95.2% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of G-28b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (75 mg), compound G-28-In (80 mg), BOP reagent (0.1 g) and Hunig'sbase (0.2 ml) were combined in dry DMF (4 ml). The reaction mixture wasstirred at room temperature for over night. The mixture was quenchedwith methanol (10 ml) and volatiles were removed under reduced pressure.The resulting oil was diluted with ethyl acetate (50 ml), washed with10% NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting crude waspurified by column chromatography using dichloromethane\methanol (1:9)as eluent to afford G-28b as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (s, 3H), 3.15 (t, 2H), 3.28 (t, 2H),3.3 (s, 3H), 3.48 (t, 2H), 3.69 (t, 2H), 3.97 (s, 3H), 7.5 (m, 1H), 7.53(m, 2H), 7.61 (d, 2H), 7.88 (s, 1H), 8.23 (s, 1H), 9.21 (s, 1H), 12.4(s, 1H).

LC-MS: 591 (M⁺+1).

HPLC: 96.0% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of Compound G-29a and G-29b Preparation of IntermediateG-29-In

Step-1

Dry methanol (10 ml) was charged to a clean and dry 3 necked roundbottom flask fitted with reflux condenser, stirring bar and a nitrogenbubbler. Sodium metal (564 mg) was added portion wise to the abovereaction mixture at room temperature. After complete dissolution ofsodium metal, tert-butyl4-(3-(methylsulfonyl)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate(1.0 g) in 5 ml methanol was added and reaction mass was heated to 60°C. Reaction mixture was allowed to stir at 60° C. for over night.Reaction mixture was cooled to room temperature and slowly quenched withice. Product was extracted with ethyl acetate and organic layer waswashed with water, brine, dried and concentrated to get pure tert-butyl4-(3-methoxy-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate asoff white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.49 (s, 9H), 3.0 (t, 4H), 3.3 (m, 4H), 4.0(s, 3H), 7.38-7.60 (m, 5H).

LC-MS: 360 (M⁺+1).

Step-2

To tert-butyl4-(3-methoxy-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate(500 mg) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was addedat 0° C. The reaction mixture was allowed to reach at room temperatureand stirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine compound G-29-In, whichwas used for the next reaction without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 3.0 (t, 4H), 3.3 (m, 4H), 4.0 (s, 3H),7.38-7.60 (m, 5H).

LC-MS: 259 (M⁺+1).

Preparation of G-29a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (95 mg), compound G-29-In (100 mg), BOP reagent (0.16 mg) andHunig's base (0.2 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography usingdichloromethane\methanol (1:9) as eluent to afford G-29a as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.08 (t, 2H), 3.2 (t, 2H), 3.46 (t, 2H),3.68 (t, 2H), 3.83 (s, 3H), 7.36 (m, 1H), 7.48 (m, 2H), 7.65 (m, 2H),8.11 (s, 1H), 8.3 (s, 1H), 8.35 (s, 1H), 9.01 (s, 1H), 13.06 (s, 1H).

LC-MS: 517 (M⁺+1).

HPLC: 97.4% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of G-29b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (116 mg), compound G-29-In (100 mg), BOP reagent (0.176 mg) andHunig's base (0.2 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography usingdichloromethane\methanol (1:9) as eluent to afford G-29b as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (s, 3H), 3.08 (t, 2H), 3.2 (t, 2H),3.46 (t, 2H), 3.68 (t, 2H), 3.83 (s, 3H), 3.98 (s, 3H), 7.36 (m, 1H),7.48 (m, 2H), 7.65 (m, 2H), 7.88 (s, 1H), 8.22 (s, 1H), 9.23 (s, 1H).

LC-MS: 543 (M⁺+1).

HPLC: 97.1% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of Compound G-30a and G-30b Preparation of IntermediateG-30-In

Step-1

1,2,3-Triazole (5 g), iodobenzene (9.72 ml) and copper iodide (0.68 g)was taken in dry DMF under Nitrogen atmosphere.1,2-(N,N-dimethyl)cyclohexyl diamine (1.02 g) and potassium phosphate(30.73 g) was added into above mixture. The reaction mixture was refluxat 110° C. for over night. TLC was checked no starting material and thereaction mixture was filtered through celite. The filtrate was dilutedwith water and product was extracted with dichloromethane. The organiclayer was evaporated and the crude product was purified by columnchromatography using 60-120 silica gel and pet ether\ethyl acetate aseluent to give 1-phenyl-1H-1,2,3-triazole as white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.47 (m, 1H), 7.5-7.6 (m, 2H), 7.9 (d, 2H),7.98 (s, 1H), 8.84 (s, 1H).

LC-MS: 145.6 (M⁺+1).

Step-2

In a 100 ml 3 necked round bottom flask, 1-phenyl-1H-1,2,3-triazole (1.2g) was taken in dry THF (25 ml) under nitrogen. n-Butyl lithium (3.36ml) was added at −78° C. and stirred for 5 minutes, then bromine (3.76ml) was added dropwise to the above reaction mixture. Reaction mixturewas stirred at −78° C. for 1 hour. TLC was checked no starting materialand the reaction mixture was quenched with saturated ammonium chloride(50 ml) and ethyl acetate was added. The organic layer was washed withsodium bisulphate, brine, dried and concentrated. The crude product waspurified by column chromatography using pet ether & ethyl acetate aseluent to give 5-bromo-1-phenyl-1H-1,2,3-triazole as yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 7.47 (m, 1H), 7.5-7.6 (m, 2H), 7.9 (d, 2H),8.05 (s, 1H).

LC-MS: 225 (M⁺+1).

Step-3

In a 100 ml single neck round bottom flask,5-bromo-1-phenyl-1H-1,2,3-triazole (0.6 g), piperazine (1.11 g) andsodium tert-butoxide (0.38 g) was taken in dry toluene (20 ml) anddegasified for 20 min. Then Pd(dba)₂ (0.11 g), BiNAP (0.16 g) was addedand again degasified for 10 min. The reaction mixture was reflux at 107°C. for over night. TLC was checked no starting material. Reactionmixture was diluted with 25 ml of water and extracted withdichloromethane. The organic layer was separated and concentrated. Thecrude product was purified by column chromatography using 60-120 silicagel and 6% methanol\chloroform as eluent to give compound G-30-In aswhite solid.

¹H NMR (400 MHz, CDCl₃): δ 2.5-2.72 (d, 8H), 7.41 (s, 1H), 7.5-7.6 (m,3H), 7.73 (d, 2H).

LC-MS: 230 (M⁺+1).

Preparation of G-30a

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (60 mg), compound G-30-In (50 mg), BOP reagent (0.094 g) andHunig's base (0.2 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography using MeOH/CHCl₃ (1:9) aseluent to afford G-30a as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.86-2.88 (t, 3H), 2.97-2.99 (t, 3H),3.45-3.38 (t, 3H), 3.67-3.7 (t, 3H), 7.52 (s, 2H), 7.6 (m, 2H), 7.78 (m,2H), 8.12 (s, 1H), 8.3-8.35 (d, 2H), 9.0 (s, 1H), 13.0 (s, 1H).

LC-MS: 487 (M⁺+1).

HPLC: 96.4% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of G-30b

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (60 mg), compound G-30-In (50 mg), BOP reagent (0.094 g) andHunig's base (0.2 ml) were combined in dry DMF (4 ml). The reactionmixture was stirred at room temperature for over night. The mixture wasquenched with methanol (10 ml) and volatiles were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml),washed with 10% NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude was purified by column chromatography using MeOH/CHCl₃ (1:9) aseluent to afford G-30b as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (s, 3H), 2.86-2.88 (t, 2H), 2.95-2.98(t, 2H), 3.4-3.42 (t, 2H), 3.65-3.67 (t, 2H), 3.97 (s, 3H), 7.52 (s,2H), 7.6 (m, 2H), 7.76-7.78 (d, 2H), 7.89 (s, 1H), 8.22 (s, 1H), 9.24(s, 1H), 12.4 (s, 1H).

LC-MS: 513 (M⁺+1).

HPLC: 97.7% (0.1% H₃PO₄/ACN; Column: YMC-PACK ODS-AQ (4.6×250) mm).

Preparation of Compound G-31 Preparation of Intermediate G-31-In

Step-1

4-Methoxy-7-bromo-6-azaindole (120 mg) was added in portions to a meltedof 4-methyl-1,2,3-triazole (219 mg) under argon at 110-120° C. Themixture was heated to 130° C. and was stirred at 130° C. for 17 hours.The reaction mixture was cooled to room temperature and the resultingresidue was purified by column chromatography using EtOAc/Hexane (6:4)mixture as eluent which afforded4-methoxy-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridineas a tan solid. ¹H NMR (400 MHz, DMSO-D6): δ 2.38 (s, 3H), 4.01 (s, 3H),6.66 (dd, 1H, J=2.9, 2.6), 7.53 (dd, 1H, J=2.9, 2.8), 7.70 (s, 1H), 8.62(s, 1H), 11.78 (bs, 1H). MS: 230.3 (M⁺+1).

Step-2

To4-methoxy-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine(0.3 g) taken in methyl THF (20 ml) and cooled to −10° C., ethylmagnesium bromide (1.5 ml, 1M solution in THF) was added drop wise bymaintaining internal temperature <−5° C. for about 15 min. The reactionmixture was stirred for another 1 hr at same temperature and pyridine(51 mg, 0.645 mmol) was added in one portion. The reaction mixture wasfurther cooled to −40° C., added methoxyoxalyl chloride (0.64 g) dropwise for about 15 min and stirred at the same temperature for 1 hr. Thereaction was quenched with isopropyl alcohol (2 ml) followed bysaturated ammonium chloride solution. Two layers were separated andaqueous layer was extracted with ethyl acetate (3×20 ml). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford off-white solid, methyl2-(4-methoxy-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate.¹H NMR (400 MHz, CDCl₃): δ1.38 (s, 3H), 2.5 (s, 3H), 3.9 (s 3H), 7.82(s, 1H), 8.39 (dd, 1H), 8.43 (s, 1H). MS: 316.3 (M⁺+1).

Step-3

To methyl2-(4-methoxy-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate(0.3 g) dissolved in 20 ml of THF/H2O mixture (1:1), lithium hydroxide(0.1 g) was added. After the reaction was stirred for 16 hours at roomtemperature, volatiles were removed under reduced pressure and theresidue was acidified using dilute HCl to pH ˜6. The resulting solid,2-(4-methoxy-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid, was filtered, dried and used for the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-D₆): δ 2.38 (s, 3H), 4.01 (s, 3H),7.53 (dd, 1H, J=2.9, 2.8), 7.70 (s, 1H), 8.62 (s, 1H), 11.78 (bs, 1H).MS: 302.3 (M⁺+1).

Preparation of Compound G-31

To a stirred solution of2-(4-methoxy-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (75 mg) in dry DMF (5 ml),1-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazine (86 mg), BOP reagent(110 mg) and DIPEA (0.1 ml) were added. The reaction mixture was stirredat room temperature for 16 hours. The solvent was removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 ml) andwashed with 10% NaHCO₃ (10 ml) and brine (10 ml). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated using rotary evaporator.The resulting crude was purified by column chromatography usingMeOH/CHCl₃ (2:8) as eluent to afford G-31 as off white solid. ¹H NMR(400 MHz, DMSO-D₆): 2.38 (s, 3H), 3.12-3.15 (m, 2H), 3.3-3.32 (m, 4H),3.65-3.68 (m, 2H), 4.01 (s, 3H), 7.59-7.62 (m, 2H), 7.77 (s, 1H),7.80-7.82 (d, 1H), 8.10-8.14 (t, 1H), 8.63-8.64 (d, 2H), 12.01 (bs, 1H).MS: 513.3 (M⁺−1).

Preparation of Compound G-31 Preparation of Intermediate G-31-In

Step-1

To tert-butyl4-(3-(methylsulfonyl)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate(500 mg) taken in dry THF (50 ml) cooled to 0° C., methyl magnesiumbromide (0.9 ml, 3.0M solution in THF) was added drop wise. The reactionmixture was slowly heated to 50° C. and continued for about 18 hrs. Thereaction mixture was cooled to 10° C. and quenched with saturatedammonium chloride. The reaction mixture was extracted with ethyl acetate(3×20 ml) and combined organic layer was washed with water, brine anddried over anhydrous sodium sulphate. The volatiles were removed underreduced pressure. The resulting crude product was purified by columnchromatography using 230-400 silica gel and 5% methanol\chloroform aseluant to afford desire tert-butyl4-(3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate. ¹HNMR (400 MHz, DMSO-d₆): δ 1.49 (s, 9H), 2.36 (s, 3H), 3.1 (t, 4H),3.31-3.36 (t, 4H), 7.38-7.60 (m, 5H). MS: 344 (M⁺+1).

Step-6

To tert-butyl4-(3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine-1-carboxylate (500mg) dissolved in dry dichloromethane (10 ml), TFA (5 ml) was added at 0°C. The reaction mixture was allowed to reach room temperature andstirred for over-night. The volatiles were completely removed andresulting residue was diluted with dichloromethane (20 ml). The organiclayer was washed with saturated NaHCO₃ (2×10 ml), brine, dried overNa₂SO₄. Evaporation of solvent gave desire amine G-32-In, which was usedfor the next reaction without further purification. ¹H NMR (400 MHz,DMSO-d₆): δ 2.39 (s, 3H), 3.28 (t, 4H), 3.31-3.36 (t, 4H), 7.38-7.60 (m,5H). MS: 244 (M⁺+1).

Preparation of Compound G-32

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (80 mg) in dry DMF (5 ml), G-32-In (75 mg), BOP reagent and DIPEA(0.1 ml) were added. The reaction was stirred at room temperature for 16hours. The solvent was removed under reduced pressure. The resulting oilwas diluted with dichloromethane (20 ml) and washed with 10% NaHCO₃ andbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated using rotary evaporator. The resulting crude was purifiedby column chromatography using MeOH/CHCl₃ (2:8) as eluent to afford G-32as yellow color solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.43 (s, 3H), 3.24-3.26 (t, 2H), 3.34-3.36(t, 2H), 3.62-3.65 (t, 2H), 3.82-3.85 (t, 2H), 7.37-7.41 (t, 2H),7.47-7.51 (t, 2H), 7.61-7.63 (s, 1H), 7.94 (s, 1H), 8.15-8.16 (d, 1H),8.36-8.37 (d, 1H), 8.76 (s, 1H).

LC-MS: 500.7 (M⁺+1), 500, 1.4 min

Example Chemistry Section H

Compounds in this section were prepared and analyzed using one of thefollowing general procedures and LC-MS condition.

General Procedure for Suzuki Coupling of Bromo Scaffold with BoronicAcids:

The mixture of1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(1 eq), boronic acid (3 eq) and cesium carbonate (3 eq), dissolved indioxane and water (volume ratio 20:1), was degassed for 30 minutes. Tothe reaction mixture Pd(dppf)Cl₂ (0.2 eq) was added and the reactionmixture was again degassed with nitrogen for 20 minutes. After thereaction mixture was heated to 80° C. in microwave for 3 hours, it wasfiltered through a celite pad and washed with ethyl acetate. Evaporationof solvent under reduced pressure afforded the crude product, which waspurified by column chromatography using MeOH/CHCl₃ (2:8) as eluent.

General Procedure for Suzuki Coupling of Bromo Scaffold with BoronicEsters:

A. The mixture of Bromo compound1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(eq), boronic ester (3 eq) and potassium carbonate (3 eq), dissolved in1,2-dimethoxy ethane and water (volume ratio 20:1), was degassed for 30minutes. To the reaction mixture Pd(PPh₃)₄ (0.2 eq) was added and againdegassed with nitrogen for 20 minutes and heated to 80° C. in microwavefor 3 hours. The reaction mixture was filtered through a celite pad andwashed with dichloromethane. Evaporation of solvent under reducedpressure afforded crude product, which was purified by columnchromatography using MeOH/CHCl₃ (2:8) as eluent.

B. The mixture of1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione(1 eq), boronic ester (3 eq) and cesium carbonate (3 eq), dissolved indioxane, dimethylformamide and water (volume ratio 2:18:1), was degassedfor 30 minutes. To the reaction mixture Pd(dppf)Cl₂ (0.2 eq) was addedand again degassed with nitrogen for 20 minutes. After the reactionmixture was heated to 90° C. in microwave for 3 hours, it was filteredthrough a celite pad and washed with ethyl acetate. Evaporation ofsolvent under reduced pressure gave crude product, which was purified bycolumn chromatography using MeOH/CH₂Cl₂ (2:8) as eluent.

Analytical LC-MS Method:

LC-MS instrument: Agilent 6320 ion Trap

Method info: A-0.1% HCOOH B-CAN FLOW-0.8 ml/min

Column: ATLANTIS C18 75×4.6 mm 5 μm

Time % B % A 0 70 30 1.0 70 30 1.5 95 05 2.5 95 05 3.0 70 30 6.0 70 30

MS (M + H)⁺ Compd Observ. (Calc'd), # Structure Rf and NMR H-1

MS: 529.1 (calc'd. 529.2) Rf = 1.1 min ¹H NMR (400 MHz, DMSO-d₆): δ3.25-3.27(t, 2 H), 3.40-3.42 (t, 4 H), 3.69-3.70 (t, 2 H), 4.0 (s, 3 H),7.61-7.63 (d, 1 H), 7.83-7.85 (d, 1 H), 8.0-8.2 (m, 1 H), 8.2 (s, 1 H),8.32-8.33 (d, 2 H), 8.65-8.68 (m, 2 H), 8.86 (s, 1 H), 12.9 (bs, 1 H).H-2

MS: 529.1 (calc'd. 529.2) Rf = 1.1 min ¹H NMR (400 MHz, DMSO-d₆): δ3.26-3.27(t, 2 H), 3.32-3.42 (t, 4 H), 3.69-3.70 (t, 2 H), 3.99 (s, 3 H),7.35-7.37 (m, 1 H), 7.61-7.64 (m, 1 H), 7.83-7.85 (m, 1 H), 8.13-8.16(m, 2 H), 8.32-8.38 (m, 2 H), 8.63-8.66 (m, 2 H), 12.85 (bs, 1 H). H-3

MS: 511.2 (calc'd. 511.2) Rf = 0.94 min ¹H NMR (400 MHz, DMSO-d₆):δ3.27- 3.37(t, 4 H), 3.42-3.44 (t, 4 H), 4.0 (s, 3 H), 7.61-7.63 (m, 1H), 7.63-7.78 (m, 1 H), 7.83-7.85 (d, 1 H), 8.13-8.16 (m, 2 H),8.32-8.38 (m, 2 H), 8.63-8.66 (d, 1 H), 8.78-8.79 (d, 1 H), 9.0 (s, 1H), 13.15 (bs, 1 H). H-4

MS: 545.1 (calc'd. 545.2) Rf = 1.1 min ¹H NMR (400 MHz, DMSO-d₆): δ3.26-3.27(t, 2 H), 3.32-3.42 (t, 4 H), 3.69-3.70 (t, 2 H), 3.99 (s, 3 H),7.55-7.57 (s, 1 H), 7.61-7.64 (m, 1 H), 7.83-7.85 (d, 2 H), 8.13-8.18(m, 2 H), 8.31-8.33 (d, 2 H), 8.63-8.8 (s, 1 H), 12.69 (bs, 1 H). H-5

MS: 541.1 (calc'd. 541.2) Rf = 1.1 min ¹H NMR (400 MHz, DMSO-d₆): δ3.26-3.27(t, 2 H), 3.32-3.42 (t, 4 H), 3.69-3.70 (t, 2 H), 3.90 (s, 3 H),4.01 (s, 3 H), 7.62- 7.68 (m, 3 H), 7.83-7.85 (d, 1 H), 8.13- 8.17 (t, 1H), 8.19 (s, 1 H), 8.31-8.33 (s, 1 H), 8.41-8.48 (d, 1 H), 8.65-8.67 (s,1 H), 12.69 (bs, 1 H). H-6

MS: 541.1 (calc'd. 541.2) Rf = 0.8 min ¹H NMR (400 MHz, DMSO-d₆): δ3.26-3.27(t, 2 H), 3.32-3.42 (t, 4 H), 3.69-3.70 (t, 2 H), 3.92 (s, 3 H),3.98 (s, 3 H), 7.50- 7.52 (d, 2 H), 7.61-7.65 (d, 2 H), 7.83-7.85 (d, 1H), 8.13-8.15 (m, 1 H), 8.17-8.175 (d, 1 H), 8.65-8.66 (d, 1 H),8.72-8.74 (d, 1 H), 12.69 (bs, 1 H). H-7

MS: 525.2 (calc'd. 525.2) Rf = 0.8 min ¹H NMR (400 MHz, DMSO-d₆): δ2.26(s, 3 H), 3.28-3.42 (t, 4 H), 3.49-3.70 (t, 4 H), 4.01 (s, 3 H),7.62-7.64 (t, 1 H), 7.65- 7.653 (d, 1 H), 7.73-7.85 (d, 1 H), 8.13- 8.15(t, 1 H), 8.19 (s, 1 H), 8.65-8.66 (d, 2 H), 8.72-8.74 (d, 2 H), 12.97(bs, 1 H). H-8

MS (M − H)⁺: 527.2 (calc'd. 527.2) Rf = 1.2 min ¹H NMR (400 MHz,DMSO-d₆): δ3.26- 3.28 (t, 2 H), 3.38-3.42 (t, 4 H), 3.69-3.71 (t, 2 H),4.01 (s, 3 H), 7.56 (s, 1 H), 7.62- 7.64 (d, 1 H), 7.65-7.653 (d, 1 H),7.73- 7.85 (d, 1 H), 8.13-8.15 (t, 1 H), 8.19 (s, 1 H), 8.34-8.39 (d, 2H), 8.65-8.66 (d, 1 H), 12.85 (bs, 1 H). H-9

MS (M − H)⁺: 524.3 (calc'd. 524.2) Rf = 0.78 min ¹H NMR (400 MHz,DMSO-d₆): δ3.23- 3.27 (t, 2 H), 3.39-3.41 (t, 4 H), 3.68-3.70 (t, 2 H),3.93 (s, 3 H), 6.47 (bs, 2 H), 6.63- 6.65 (d, 1 H), 7.62-7.64 (m, 2 H),7.82- 7.87 (t, 2 H), 8.0 (s, 1 H), 8.13-8.16 (m, 1 H), 8.20 (s, 1 H),8.34-8.35 (d, 1 H), 8.65-8.66 (d, 1 H), 12.85 (bs, 1 H). H-10

MS: 541.2 (calc'd. 541.2) Rf = 0.78 min ¹H NMR (400 MHz, DMSO-d₆):δ3.23- 3.27 (t, 2 H), 3.39-3.41 (t, 4 H), 3.68-3.70 (t, 2 H), 3.94 (s, 3H), 3.96 (s, 3 H), 6.98- 7.0 (d, 1 H), 7.61-7.64 (t, 1 H), 7.83-7.85 (d,1 H), 8.10-8.16 (m, 3 H), 8.26 (s, 1 H), 8.58 (s, 1 H), 8.65-8.66 (d, 1H), 12.82 (bs, 1 H). H-11

MS: 536.2 (calc'd. 536.2) Rf = 1.14 min 1H NMR (400 MHz, DMSO-d6):δ3.25- 3.27(t, 2 H), 3.39-3.41 (t, 4 H), 3.69-3.71 (t, 2 H), 4.0 (s, 3H), 7.61-7.64 (t, 1 H), 7.83-7.85 (d, 1 H), 8.12-8.14 (t, 1 H),8.15-8.20 (m, 2 H), 8.35 (s, 1 H), 8.43- 8.45 (d, 1 H), 8.65-8.66 (d, 1H), 9.17 (s, 1 H), 12.95 (bs, 1 H). H-12

MS: 525.2 (calc'd. 525.2) Rf = 0.98 min ¹H NMR (400 MHz, DMSO-d₆): δ2.57(s, 3 H), 3.25-3.27 (t, 2 H), 3.39-3.41 (t, 4 H), 3.69-3.71 (t, 2 H),3.99 (s, 3 H), 7.60-7.64 (m, 2 H), 7.67 (s, 1 H), 7.83-7.85 (d, 1 H),8.12-8.17 (m, 1 H), 8.18 (s, 1 H), 8.29- 8.30 (d, 1 H), 8.58-8.65 (d, 1H), 8.66 (d, 1 H), 12.77 (bs, 1 H). H-13

MS (M − H)⁺: 529.2 (calc'd. 529.2) Rf = 0.98 min ¹H NMR (400 MHz,DMSO-d₆): δ3.24- 3.27 (t, 2 H), 3.39-3.41 (t, 4 H), 3.69-3.71 (t, 2 H),3.97 (s, 3 H), 7.34-7.37 (dd, 1 H), 7.61-7.64 (dd, 1 H), 7.82-7.84 (d, 1H), 8.12-8.16 (m, 2 H), 8.30 (s, 1 H), 8.33-8.38 (m, 1 H), 8.62-8.65 (m,2 H), 12.85 (bs, 1 H).

Biology

“μM” means micromolar;

“mL” means milliliter;

“μl” means microliter;

“mg” means milligram;

The materials and experimental procedures used to obtain the resultsreported in Tables 3-4 are described below.

Cells:

-   -   Virus production—Human embryonic Kidney cell line, 293T, was        propagated in Dulbecco's Modified Eagle Medium (Invitrogen,        Carlsbad, Calif.) containing 10% fetal Bovine serum (FBS, Sigma,        St. Louis, Mo.).    -   Virus infection—Human epithelial cell line, HeLa, expressing the        HIV-1 receptor CD4 was propagated in Dulbecco's Modified Eagle        Medium (Invitrogen, Carlsbad, Calif.) containing 10% fetal        Bovine serum (FBS, Sigma, St. Louis, Mo.) and supplemented with        0.2 mg/mL Geneticin (Invitrogen, Carlsbad, Calif.).        Virus-Single-round infectious reporter virus was produced by        co-transfecting human embryonic Kidney 293 cells with an HIV-1        envelope DNA expression vector and a proviral cDNA containing an        envelope deletion mutation and the luciferase reporter gene        inserted in place of HIV-1 nef sequences (Chen et al, Ref. 41).        Transfections were performed using lipofectAMINE PLUS reagent as        described by the manufacturer (Invitrogen, Carlsbad, Calif.).        Experiment

-   1. HeLa CD4 cells were plated in 96 well plates at a cell density of    1×10⁴ cells per well in 100 μl Dulbecco's Modified Eagle Medium    containing 10% fetal Bovine serum and incubated overnight.

-   2. Compound was added in a 2 μl dimethylsulfoxide solution, so that    the final assay concentration would be ≦10 μM.

-   3. 100 μl of single-round infectious reporter virus in Dulbecco's    Modified Eagle Medium was then added to the plated cells and    compound at an approximate multiplicity of infection (MOI) of 0.01,    resulting in a final volume of 200 μl per well.

-   4. Virally-infected cells were incubated at 37 degrees Celsius, in a    CO₂ incubator, and harvested 72 h after infection.

-   5. Viral infection was monitored by measuring luciferase expression    from viral DNA in the infected cells using a luciferase reporter    gene assay kit, as described by the manufacturer (Roche Molecular    Biochemicals, Indianapolis, Ind.). Infected cell supernatants were    removed and 50 μl of lysis buffer was added per well. After 15    minutes, 50 μl of freshly-reconstituted luciferase assay reagent was    added per well. Luciferase activity was then quantified by measuring    luminescence using a Wallac microbeta scintillation counter.

-   6. The percent inhibition for each compound was calculated by    quantifying the level of luciferase expression in cells infected in    the presence of each compound as a percentage of that observed for    cells infected in the absence of compound and subtracting such a    determined value from 100.

-   7. An EC₅₀ provides a method for comparing the antiviral potency of    the compounds of this disclosure. The effective concentration for    fifty percent inhibition (EC₅₀) was calculated with the Microsoft    Excel Xlfit curve fitting software. For each compound, curves were    generated from percent inhibition calculated at 10 different    concentrations by using a four parameter logistic model (model 205).    The EC₅₀ data for the compounds is shown in Table 4. Table 3 is the    key for the data in Table 4.    Results

TABLE 3 Biological Data Key for EC₅₀s Compounds with Compounds with EC₅₀<= 0.5 μM EC₅₀s > 0.5 μM Group A Group B

TABLE 4 EC₅₀ Compd Group # Structure from Table 3 A-1

A A-2

B A-3

A A-4

A A-5

A A-6

A A-7

A A-8

A A-9

A A-10

A A-11

A A-12

A A-13

A A-14

A A-15

A A-16

A A-17

A A-18

A A-19

A A-20

A A-21

A A-22

A A-23

B A-24

B A-25

A A-26

A A-28

A A-29

A A-30

A A-31

A A-32

A A-27

A A-33

B A-34

B A-35

A A-36

B A-37

A A-38

A A-39

B B-2

A B-17

A A-40

B A-41

B A-42

B B-2

A B-3

A B-4

A B-5

A A-43

A B-8

A B-9

A B-10

A B-11

A B-12

A B-13

A C-1

A A-44

A A-45

A B-18

B B-19

A B-15

A A-46

A B-24

A A-47

A B-14

A B-21

A B-16

A B-22

A B-20

A B-25

A B-26

A B-23

A A-48

A A-49

A B-27

A A-50

A A-51

A A-52

B D-1

A D-2

A D-3

A D-4

A D-5

A D-6

A D-7

A D-8

A D-9

B D-10

A D-11

B D-12

B D-13

B D-14

A D-15

A D-16

B D-17

A D-18

A D-19

A D-20

A D-21

B D-22

B D-23

A D-24

A D-26

B D-27

A D-28

B D-29

B D-30

A D-31

B D-32

A D-33

A D-34

A D-35

A D-36

B D-37

B D-38

B D-39

B D-40

B D-41

B D-42

B D-43

B D-44

B D-45

B D-46

B D-47

A D-48

A D-49

A D-50

B D-51

B A-53

A A-54

A A-55

A A-56

B A-57

A A-58

A A-59

A A-60

A A-61

A A-62

A A-63

A A-64

A A-66

A A-67

B A-68

A A-69

A A-70

A A-71

A A-72

A A-73

A A-74

B E-1

A E-2

A E-3

A E-4

A E-5

A E-6

A E-7

A E-8

A E-9

A E-10

B E-11

B E-12

B E-12a

A E-12b

A E-12c

A E-12d

A E-13

A E-14

A E-15

A E-16

A E-17

A F-1

A F-2

A F-3

A F-4

A F-5

A F-6

A F-7

A F-8

A F-9

A F-10

A F-11

A F-12

A F-13

A F-14

A F-15

A F-16

A B-28

A B-29

A B-30

A B-31

A B-32

B B-33

A B-34

A B-35

A B-36

A B-37

A B-38

A B-39

A B-40

A B-41

A B-42

A B-43

A B-44

A B-45

A B-46

B B-47

A B-48

A B-49

A B-50

A B-51

A B-52

A B-53

A B-54

A B-55

A B-56

A B-57

A B-58

A B-59

A B-60

A B-61

A B-62

A B-63

A B-64

A B-65

A B-66

A B-67

A B-68

A B-69

A B-70

A B-71

A B-72

A B-73

A B-74

B B-75

A B-76

B B-77

A B-78

A B-79

A B-80

A B-81

A B-82

A B-83

A B-84

A B-85

A B-86

A B-87

A B-88

A B-89

A B-90

A B-91

A B-92

A G-1a

A G-1b

A G-2a

A G-2b

A G-2c

A G-3a

A G-3b

A G-4a

A G-4b

A G-4c

B G-4d

A G-5a

A G-5b

A G-6a

A G-6b

A G-7a

A G-7b

A G-8a

A G-8b

A G-9a

A G-9b

A G-10a

B G-10b

B G-11a

A G-11b

B G-12a

A G-12b

A G-13a

A G-13b

A G-14a

A G-14b

A G-15a

A G-15b

A G-16

A G-17a

B G-17b

A G-18a

A G-18b

A G-19a

A G-19b

A G-20

A G-21

A G-22a

A G-22b

A G-23

A G-24a

A G-24b

A G-25a

A G-25b

A G-26a

A G-26b

A G-27a

A G-27b

A G-28a

A G-28b

A G-29a

A G-29b

A G-30a

A G-30b

A G-31

A G-32

A H-1

A H-2

A H-3

A H-4

A H-5

A H-6

A H-7

A H-8

A H-9

A H-10

A H-11

A H-12

A H-13

A

1. A compound which is selected from the group consisting of:


2. A compound which is selected from the group consisting of:


3. A compound which is selected from the group consisting of:


4. A compound which is selected from the group consisting of:


5. A pharmaceutical composition which comprises an antiviral effectiveamount of a compound of claim 1, or pharmaceutically acceptable saltsthereof, and one or more pharmaceutically acceptable carriers,excipients or diluents.
 6. A pharmaceutical composition which comprisesan antiviral effective amount of a compound of claim 2, orpharmaceutically acceptable salts thereof, and one or morepharmaceutically acceptable carriers, excipients or diluents.
 7. Apharmaceutical composition which comprises an antiviral effective amountof a compound of claim 3, or pharmaceutically acceptable salts thereof,and one or more pharmaceutically acceptable carriers, excipients ordiluents.
 8. A pharmaceutical composition which comprises an antiviraleffective amount of a compound of claim 4, or pharmaceuticallyacceptable salts thereof, and one or more pharmaceutically acceptablecarriers, excipients or diluents.
 9. The composition of claim 5, furthercomprising a second compound having anti-HIV activity.
 10. Thecomposition of claim 6, further comprising a second compound havinganti-HIV activity.
 11. The composition of claim 7, further comprising asecond compound having anti-HIV activity.
 12. The composition of claim8, further comprising a second compound having anti-HIV activity.
 13. Amethod for treating a mammal infected with HIV virus comprisingadministering to said mammal an antiviral effective amount of a compoundof claim 1, or pharmaceutically acceptable salts thereof, and one ormore pharmaceutically acceptable carriers, excipients or diluents.
 14. Amethod for treating a mammal infected with HIV virus comprisingadministering to said mammal an antiviral effective amount of a compoundof claim 2, or pharmaceutically acceptable salts thereof, and one ormore pharmaceutically acceptable carriers, excipients or diluents.
 15. Amethod for treating a mammal infected with HIV virus comprisingadministering to said mammal an antiviral effective amount of a compoundof claim 3, or pharmaceutically acceptable salts thereof, and one ormore pharmaceutically acceptable carriers, excipients or diluents.
 16. Amethod for treating a mammal infected with HIV virus comprisingadministering to said mammal an antiviral effective amount of a compoundof claim 4, or pharmaceutically acceptable salts thereof, and one ormore pharmaceutically acceptable carriers, excipients or diluents. 17.The method of claim 13, comprising administering to said mammal anantiviral effective amount of said compound in combination with anantiviral effective amount of an AIDS treatment agent selected from thegroup consisting of: an AIDS antiviral agent; an anti-infective agent;an immunomodulator; and an HIV entry inhibitor.
 18. The method of claim14, comprising administering to said mammal an antiviral effectiveamount of said compound in combination with an antiviral effectiveamount of an AIDS treatment agent selected from the group consisting of:an AIDS antiviral agent; an anti-infective agent; an immunomodulator;and an HIV entry inhibitor.
 19. The method of claim 15, comprisingadministering to said mammal an antiviral effective amount of saidcompound in combination with an antiviral effective amount of an AIDStreatment agent selected from the group consisting of: an AIDS antiviralagent; an anti-infective agent; an immunomodulator; and an HIV entryinhibitor.
 20. The method of claim 16, comprising administering to saidmammal an antiviral effective amount of said compound in combinationwith an antiviral effective amount of an AIDS treatment agent selectedfrom the group consisting of: an AIDS antiviral agent; an anti-infectiveagent; an immunomodulator; and an HIV entry inhibitor.
 21. The compoundof claim 1, wherein said compound is selected from the group


22. The compound of claim 2, wherein said compound is